sirolimus and temsirolimus

Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review.. To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.. We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020.. We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy.. Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach.. We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 mon. Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Axitinib; Bevacizumab; Bias; Carcinoma, Renal Cell; Everolimus; Humans; Indazoles; Ipilimumab; Kidney Neoplasms; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Quinolines; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that can be either aggressive or indolent. Although MCL usually responds well to initial treatment with chemotherapy-based regimens, the disease often relapses or becomes refractory within a few years. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. WIthout head-to-head clinical trial data, estimation of the comparative efficacy and safety of new therapeutic entities provides valuable information for patients, clinicians, and health care payers. The objective of this analysis was to compare the efficacy and safety of acalabrutinib versus other targeted therapies employed for the treatment of relapsed/refractory MCL by using matching-adjusted indirect comparisons.. Individual data from 124 patients treated with acalabrutinib in the Phase II ACE-LY-004 trial were adjusted to match average baseline characteristics of populations from studies using alternative targeted treatment regimens for relapsed/refractory MCL (for monotherapy: ibrutinib, bortezomib, lenalidomide, and temsirolimus; for combination therapies: ibrutinib + rituximab, bendamustine + rituximab, and lenalidomide + rituximab). Patient populations were matched on age, sex, race, Eastern Cooperative Oncology Group performance status, Simplified MCL International Prognostic Index score, tumor bulk, lactate dehydrogenase concentration, extranodal disease, bone marrow involvement, and number of previous treatment regimens. Outcomes assessed included overall response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), and adverse events.. After matching, acalabrutinib was associated with significant increases in ORR and CR rate (estimated treatment difference [95% CI]) versus ibrutinib (ORR, 9.3% [0.3-18.3]; CR, 14.9% [5.4-24.3]), bortezomib (ORR, 50.6% [40.2-61.0]; CR, 18.8% [9.1-28.5]), lenalidomide (ORR, 38.1% [27.1-49.1]; CR, 43.5% [34.8-52.3]), and temsirolimus (ORR, 40.7% [31.0-50.4]; CR, 27.1% [19.2-35.0]). PFS (hazard ratio [95% CI]) with acalabrutinib was significantly increased versus bortezomib (0.36 [0.26-0.51]), lenalidomide (0.65 [0.48-0.89]), lenalidomide + rituximab (0.57 [0.35-0.93]), and temsirolimus (0.33 [0.24-0.45]). Acalabrutinib was associated with significantly increased OS (hazard ratio) versus bortezomib (0.36 [0.22-0.61]) and temsirolimus (0.32 [0.23-0.44]). The overall safety profile of acalabrutinib was similar or better compared with the monotherapies; however, infection risk increased versus bendamustine + rituximab, and anemia increased risk versus lenalidomide + rituximab and ibrutinib + rituximab.. This comparison of targeted therapies used in the treatment of relapsed/refractory MCL showed that acalabrutinib has the potential to provide increased response rates, with trends for increased PFS and OS, and an improved safety profile.

Topics: Adenine; Antineoplastic Agents; Benzamides; Bortezomib; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrazines; Pyrazoles; Pyrimidines; Rituximab; Sirolimus; Treatment Outcome

Traditional treatment of malignancies with chemotherapeutic agents is often affected by the damage inflicted on non-cancerous cells. Toxicities of the oral cavity, such as mucositis and stomatitis, are some of the most significant and unavoidable toxicities associated with anti-cancer therapies. For such reason, in the last decades, newer targeted agents have been developed aiming to decrease the rates of side effects on healthy cells. Unfortunately, targeted anti-cancer therapies also showed significant rate of toxicity on healthy tissues. mTOR inhibitors showed some adverse events, such as hyperglycemia, hyperlipidemia, hypophosphatemia, hematologic toxicities, and mucocutaneous eruption, but the most important are still stomatitis and skin rash, often reported as dose-limiting side effects.. A search of the literature was performed by authors on the PubMed online database using the following key words: "sirolimus" OR "everolimus" OR "temsirolimus" OR "deforolimus" OR "ridaforolimus" combined with the Boolean operator AND with the terms: "stomatitis" OR "mucositis" OR "oral pain." Titles and abstracts of 382 potentially relevant studies were screened; of these, 114 studies were excluded because they did not report the inclusion criteria. In the second round, 268 studies were read full-text, but only 135 reported the inclusion criteria and were included for data extraction. Of the included studies, 95 referred to everolimus use, 16 to ridaforolimus, and 26 to temsirolimus (two studies referred to both everolimus and temsirolimus).. The incidence rate of stomatitis according to the agent used was 25.07% (3,959/15,787) for everolimus, 27.02% (724/2,679) for temsirolimus, and 54.76% (598/1,092) for ridaforolimus. All the three agents analyzed showed high rates of low-grade stomatitis (G1-G2), while the onset of severe stomatitis (G3-G4) was rare.. Analysis of the reports with patients treated with everolimus, temsirolimus, and ridaforolimus showed a clear prevalence of stomatitis grade 1 or 2. These data differ from that of patients treated with conventional chemotherapy in which mucositis is predominantly of grade 3 or 4.

Topics: Antineoplastic Agents; Everolimus; Humans; Severity of Illness Index; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

The majority of US adult cancer patients today are diagnosed and treated outside the context of any clinical trial (that is, in the real world). Although these patients are not part of a research study, their clinical data are still recorded. Indeed, data captured in electronic health records form an ever-growing, rich digital repository of longitudinal patient experiences, treatments, and outcomes. Likewise, genomic data from tumor molecular profiling are increasingly guiding oncology care. Linking real-world clinical and genomic data, as well as information from other co-occurring data sets, could create study populations that provide generalizable evidence for precision medicine interventions. However, the infrastructure required to link, ensure quality, and rapidly learn from such composite data is complex. We outline the challenges and describe a novel approach to building a real-world clinico-genomic database of patients with cancer. This work represents a case study in how data collected during routine patient care can inform precision medicine efforts for the population at large. We suggest that health policies can promote innovation by defining appropriate uses of real-world evidence, establishing data standards, and incentivizing data sharing.

Topics: Carcinoma, Non-Small-Cell Lung; Electronic Health Records; Female; Follow-Up Studies; Genomics; Humans; Information Dissemination; Lung Neoplasms; Molecular Targeted Therapy; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Sirolimus; Treatment Outcome

Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients.. To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit.. We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information.. We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC.. We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables.. We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC.Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence).There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL.IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with IFN-α plus bevacizumab or standard targeted therapy (sunitinib) may lead to similar one-year overall mortality (RR 0.37, 95% CI 0.13 to 1.08; 1 study; 83 participants; low-quality evidence) and AEs of grade 3 or greater (RR 1.18, 95% CI 0.85 to 1.62; 1 study; 82 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everoli. Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.

Topics: Antineoplastic Agents; Bevacizumab; Cancer Vaccines; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Humans; Immunologic Factors; Immunotherapy; Indoles; Interferon-alpha; Kidney Neoplasms; Longevity; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib

The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway that has regulatory roles in cell survival, proliferation, and differentiation, and a critical role in tumorigenesis. In cancer, multiple studies have investigated the therapeutic targeting of the PI3K pathway, and multiple inhibitors targeting PI3K and its isoforms, protein kinase B/AKT, mammalian target of rapamycin (mTOR), and other pathway proteins have been developed. For the treatment of solid tumors, only allosteric mTOR inhibitors, such as everolimus and temsirolimus, are currently approved for clinical use. This review describes the PI3K inhibitors that have progressed from the laboratory to late-stage clinical trials, and discusses the challenges that have prevented other compounds from doing the same. Challenges to the therapeutic effectiveness of some PI3K inhibitors include the absence of reliable and effective biomarkers, their limited efficacy as single agents, insufficient development of rational therapeutic combinations, the use of schedules with a variety of off-target effects, and suboptimal therapeutic exposures. Therefore, with regard to PI3K inhibitors currently in late-stage clinical trials, the identification of appropriate biomarkers of efficacy and the development of optimal combination regimens and dosing schedules are likely to be important for graduation into clinical practice.

Topics: Animals; Clinical Trials, Phase II as Topic; Drug Approval; Everolimus; Female; Follow-Up Studies; Humans; Male; Molecular Targeted Therapy; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Survival Analysis; Treatment Outcome; United States; United States Food and Drug Administration

The network meta-analysis was conducted to compare the short-term efficacy of different single-drug targeted therapies in the treatment of renal cell carcinoma (RCC). We initially searched databases for randomized controlled trials (RCTs) on different single-drug targeted therapies in treating RCC. The meta-analysis combined the direct and indirect evidence to calculate the pooled odds ratios (OR) and draw surface under the cumulative ranking curves (SUCRA). A total of 14 eligible RCTs were ultimately selected. The partial response (PR) of Cabozantinib in the treatment of RCC was better than Sunitinib (OR = 2.7, 95%CI = 1.0-7.8), Everolimus (OR = 8.1, 95%CI = 3.1-25.0), and Temsirolimus (OR = 4.8, 95%CI = 1.0-31.0); the overall response rate (ORR) of Cabozantinib was better than Sorafenib, Sunitinib, Everolimus, and Temsirolimus (OR = 5.5, 95%CI = 1.1-27.0; OR = 2.6, 95%CI = 1.1-6.6; OR = 8.3, 95%CI = 3.5-20.0; OR = 5.7, 95%CI = 1.3-28.0 respectively). In addition, as for complete response (CR), PR, stable disease (SD), progressive disease (PD), ORR, and disease control rate (DCR), Cabozantinib had the best short-term efficacy among nine single-drug targeted therapies in the treatment of RCC (CR: 50.3%; PR: 93.6%; SD: 75.1%; PD: 68.0%; ORR: 95.5%; DCR: 73.2%); while Everolimus had the worst short-term efficacy (CR: 33.6%; PR: 22.3%; SD: 78.0%; PD: 35.9%; ORR: 22.9%; DCR: 19.9%). Our network meta-analysis indicated that Cabozantinib might have better short-term efficacy than other regimens in the treatment of RCC, while Everolimus might have poor short-term efficacy.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Network Meta-Analysis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).. A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.. Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.. Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Decision Trees; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Niacinamide; Nivolumab; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Non-clear cell renal cell carcinoma includes several histological variants. Tumor biology has significant effect on the duration of the disease. Prognosis at formally similar disease stages may differ despite same surgical treatment approaches to clear and non-clear cell renal cell carcinomas. Tumor sensitivity to pharmacotherapy also depends on the histological subtype. This article offers detailed discussion on current treatment options for patients with papillary, chromophobe, and other types of renal cell carcinoma.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Neoplasm Staging; Nephrectomy; Nivolumab; Protein Kinase Inhibitors; Sirolimus

While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown.. To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC.. Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta-analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken.. The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant.. This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed.. We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need.

Topics: Anilides; Antineoplastic Agents; Axitinib; Benzimidazoles; Bevacizumab; Carcinoma, Renal Cell; Comparative Effectiveness Research; Disease-Free Survival; Erlotinib Hydrochloride; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Pyrrolidinones; Quinolines; Quinolones; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Molecular targeted therapies have improved progression-free survival (PFS) without translating systematically into overall survival (OS) for patients with metastatic renal cell carcinoma (mRCC). In this population, patient-reported outcomes (PROs) have become a significant outcome. We evaluated the methodological quality of the assessment of PROs in randomized controlled trials (RCTs) and the clinical benefit of the different treatments including survival and quality of life (QoL).. A systematic review identified RCTs published between January 2005 and July 2014. They were evaluated according to 11 items derived from the 2013 CONSORT PROs reporting guidelines. Survival outcomes and PROs main results were analyzed and the magnitude of clinical benefit was assessed with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).. 12 RCTs were included with a total of 22 publications. The mean CONSORT score for all items was 4.5 on an 11-point scale. No publication reported the power of the PROs analysis and only one reported a PRO hypothesis. 50% of studies did not interpret PROs in relation to clinical outcomes and only 18% discussed specific limitations of PROs and their implications for generalizability. By adding the QoL criterion to PFS, 4 trials (36.4%) obtained a high level of proven clinical benefit according to the ESMO-MCBS.. The methodology for assessing PROs in mRCC is not optimal. Efforts should focus on defining PROs endpoint and increasing the quality of reporting of QoL. New-generation therapies in mRCC should demonstrate a gain not only in survival but also in QoL to be included in the therapeutic arsenal.

Topics: Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Treatment Outcome

It is widely demonstrated that the PI3K-AKT-mTOR signalling is critical in normal myeloid and lymphoid development and function. Thus, it is not strange that this pathway is often deregulated in haematological tumours, providing a strong preclinical rationale for the use of drugs targeting the PI3K-AKT-mTOR axis in haematological malignancies. The main focus of this review is to examine the mammalian target of rapamycin (mTOR, also termed mechanistic target of rapamycin [MTOR]) signalling pathways and to provide a brief overview of rapalogs and second-generation mTOR inhibitors used to target its aberrant activation in cancer treatment. We will also discuss the results obtained with the use of these agents in patients with acute leukaemia, Hodgkin lymphoma, non-Hodgkin lymphomas, multiple myeloma and Waldenström macroglobulinaemia. Ongoing clinical trials in haematological malignancies that are investigating first- and second-generation mTOR inhibitors as single agents and as components of combination regimens are also presented.

Topics: Antibiotics, Antineoplastic; Clinical Trials as Topic; Everolimus; Hematologic Neoplasms; Humans; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Activation of PI3K/Akt/mTOR (mechanistic target of rapamycin) signaling cascade has been shown in tumorigenesis of numerous malignancies including glioblastoma (GB). This signaling cascade is frequently upregulated due to loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK. mTORC2 plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. Both complexes control each other as Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Another significant component of mTORC2 is Sin1, which is crucial for mTORC2 complex formation and function. Allosteric inhibitors of mTOR, rapamycin and rapalogs, have essentially been ineffective in clinical trials of patients with GB due to their incomplete inhibition of mTORC1 or unexpected activation of mTOR via the loss of negative feedback loops. Novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6K

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Movement; Cell Proliferation; Clinical Trials as Topic; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Indoles; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Purines; Signal Transduction; Sirolimus

Targeted therapies have substantially improved outcomes in metastatic renal cell carcinoma (mRCC). As expected, poor-risk patients have the worst outcomes. Temsirolimus is currently the only agent licensed for treatment of poor-risk mRCC patients. It is associated with meaningful improvements in survival and quality of life, highlighting the importance of correctly stratifying risk in mRCC patients so they receive optimal treatment. Currently, data for other targeted therapies in poor-risk patients are relatively sparse. Optimizing outcomes in these patients is the subject of ongoing research, including studies of biomarkers and studies to elucidate the role of nephrectomy and neoadjuvant targeted therapy in poor-risk mRCC patients. The impacts of novel combinations including temsirolimus have also been explored to further improve outcomes.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease Management; Humans; Kidney Neoplasms; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Risk Assessment; Sirolimus; Treatment Outcome

Over the last few years, the most recent advances of the molecular mechanisms involved in renal cell carcinoma have led to the use of new drugs targeting VEGF, such as bevacizumab plus interferon, sorafenib, sunitinib, pazopanib, and axitinib, or the mTOR, such as temsirolimus and everolimus. The purpose of this review is to analyze the results of Phase III trial with these targeted agents, and on the management of the treatment and, in particular, when to start and to stop therapy and the use of alternative schedule of sunitinib. Recent developments in immunotherapy are also discussed.

Topics: Axitinib; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was conducted to assess the clinical efficacy, safety and effect of all first-line treatments evaluated to date on health-related quality of life (HRQoL). A systematic search of Embase, Cochrane and MEDLINE databases was performed to identify randomized controlled trials (1980-2015) evaluating any targeted therapy/immunotherapy against placebo or any other targeted intervention/immunotherapy in treatment-naive patients with metastatic renal cell carcinoma. Conference proceedings from major cancer congresses (2007-2015) were handsearched. Sixteen randomized controlled trials were identified, mostly phase III. Overall, targeted therapies were associated with either improved [sunitinib, bevacizumab+interferon α (IFNα) and temsirolimus] or comparable (sorafenib) progression-free survival (PFS) versus IFNα monotherapy. Sunitinib demonstrated comparable PFS and overall survival to pazopanib, comparable PFS to sorafenib and shorter PFS compared with bevacizumab+IFNα (although no conclusions were made with regard to superiority/inferiority). Compared with sorafenib, tivozanib demonstrated a significantly longer PFS, and both tivozanib and axitinib demonstrated higher response rates. Nintedanib demonstrated comparable PFS and overall survival to sunitinib in a phase II trial. Temsirolimus, sunitinib and sorafenib treatment led to better HRQoL versus IFNα; pazopanib was associated with better HRQoL versus sunitinib. No direct meta-analyses or indirect treatment comparison analysis were undertaken because of noncomparability of the trials. In general, targeted therapies demonstrated favourable clinical efficacy and improved HRQoL compared with IFNα monotherapy. The newer therapies, tivozanib and axitinib (but not nintedanib), appeared to exhibit greater clinical benefit (response rate) than older tyrosine kinase inhibitors.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Quality of Life; Quinazolines; Quinolines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

No head-to-head clinical trials are available to help physicians in the decision-making process of first-line therapy in poor-prognosis metastatic renal cell carcinoma (RCC). The objectives of our study were to identify experts' prescribing practices and to review available clinical data in first-line therapies for poor-prognosis metastatic RCC (mRCC).. Thirteen RCC experts were asked to fill in a self-administered questionnaire evaluating prescribing practices. A systematic review was performed in July 2015 in MEDLINE for clinical trials evaluating first-line strategy in poor-prognosis mRCC.. Ten out of 13 experts completed the questionnaire (76.9%). Sunitinib was the most frequently prescribed first-line therapy (8/10; 80%). The main reason for prescribing sunitinib most frequently was the evidence of effectiveness for the majority (5/8 experts). A total of 21 articles were found suitable. Only one phase III randomized controlled trial in which all patients had a poor prognosis was retrieved. Temsirolimus increases progression-free survival and overall survival compared to IFN-alpha. Increased PFS with sunitinib in poor-prognosis patients was shown in a subgroup analysis of the pivotal trial. An expanded-access trial confirmed this result.. Experts tend to prefer sunitinib as first-line therapy even in poor-prognosis mRCC. In light of the systematic review, no targeted therapy appears to be more effective than another. The upcoming challenge is to discover more effective new drugs since the overall survival of poor-prognosis mRCC still remains extremely limited.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indoles; Kidney Neoplasms; Male; Practice Patterns, Physicians'; Prognosis; Pyrroles; Sirolimus; Sunitinib; Treatment Outcome

Patients with squamous cell carcinoma of the head and neck (SCCHN) typically present with locally advanced (LA) stage III or IV disease and are treated with combined-modality therapy with chemotherapy, radiotherapy, and surgery (if resectable). These aggressive, upfront treatment measures are often associated with substantial morbidity, and about half the patients develop locoregional or distant recurrences. Thus, new therapeutic strategies are needed that offer similar efficacy benefits with less toxicity. Current research is focused on selectively targeting signaling pathways involved in the proliferation and malignant transformation of SCCHN cells and the tumor microenvironment. For example, the ErbB receptor pathway has been implicated in the development and progression of SCCHN, and several agents targeting this pathway and downstream effectors are in various phases of clinical investigation. Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is the only currently approved targeted therapy for the treatment of LA SCCHN. Additional agents targeting EGFR and other ErbB family members, including monoclonal antibodies (eg, panitumumab, nimotuzumab) and small-molecule tyrosine kinase inhibitors (eg, erlotinib, afatinib, lapatinib) are being studied in LA SCCHN with varying results. Other treatment strategies for LA SCCHN include targeting downstream effectors of signaling and resistance mechanisms to EGFR inhibitors (eg, mammalian target of rapamycin, Src family, and Aurora kinase family). Data from ongoing and future clinical trials will continue to refine current treatment paradigms for LA SCCHN and provide new therapeutic options and potential predictive biomarkers to improve patient efficacy and safety and abrogate resistance.

Topics: Afatinib; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azepines; Carcinoma, Squamous Cell; Cetuximab; Dasatinib; ErbB Receptors; Erlotinib Hydrochloride; Head and Neck Neoplasms; Humans; Lapatinib; Molecular Targeted Therapy; Panitumumab; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Quinazolinones; Signal Transduction; Sirolimus

Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab. The identification of predictive and prognostic factors of survival is increasing, and both clinical predictive factors and pathology-related prognostic factors are being evaluated. Serum-based biomarkers and certain histologic subtypes of RCC, as well as clinical factors such as dose intensity and the development of some class effect adverse events, have been identified as predictors of survival. Expression levels of microRNAs, expression of chemokine receptor 4, hypermethylation of certain genes, VEGF polymorphisms, and elevation of plasma fibrinogen or d-dimer have been shown to be prognostic indicators of survival. In the future, prognosis and treatment of patients with mRCC might be based on genomic classification, especially of the 4 most commonly mutated genes in RCC (VHL, PBRM1, BAP1, and SETD2). Median overall survival has improved for patients treated with a first-line targeted agent compared with survival of patients treated with first-line interferon-α, and results of clinical trials have shown a survival benefit of sequential treatment with targeted agents. Prognosis of patients with mRCC will likely improve with optimization and individualization of current sequential treatment with targeted agents.

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; DNA-Binding Proteins; Everolimus; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; MicroRNAs; Molecular Targeted Therapy; Mutation; Niacinamide; Nivolumab; Nuclear Proteins; Phenylurea Compounds; Precision Medicine; Prognosis; Pyridines; Pyrimidines; Pyrroles; Quinolines; Receptors, CCR4; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

The risk of infection attributable to mTOR inhibitors has not been determined. Databases from PubMed and abstracts presented at the American Society of Clinical Oncology meetings were searched. Eligible studies included randomized controlled trials, in which everolimus or temsirolimus was compared with placebo. A total of 12 trials were included. The attributable incidences of all-grade and high-grade infections to mTOR inhibitors were 9.3% (95% confidence interval (CI): 5.8-14.6%) and 2.3% (95% CI: 1.2-4.4%) respectively. The risk varied widely with tumor types (p <.001). There was substantial risk of infection attributable to mTOR inhibitors everolimus and temsirolimus.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Humans; Incidence; Infections; Neoplasms; Odds Ratio; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Risk; Sirolimus; TOR Serine-Threonine Kinases

In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has provided a new hope and significantly enhanced the prognosis of the disease. Three class of targeted therapy were developed, including multi-targeted tyrosine kinase inhibitors (TKI), the mammalian target of rapamycin (mTOR) complex-1 kinase inhibitors, and the humanized antivascular endothelial growth factor (VEGF) monoclonal antibody. Hence, the objective of this article was to critically examine the current evidence of targeted therapy treatment for patients with mRCC. In the majority of trials evaluating targeted therapy, patients were stratified according to Memorial Sloan Kattering Cancer Center (MSKCC) risk model and the recommendation of targeted treatment based on risk features. In first-line setting (no previous treatment), sunitinib, pazopanib, or bevacizumab plus IFN-α were recommended as treatment options for patient with favorable- or intermediate- risk features and clear cell histology. Patients who progressed after previous cytokine therapy would have sorafenib or axitinib as treatment options. Clear-cell mRCC with favorable- or intermediate- risk features and failure with first-line TKI therapy might be treated with sorafenib, everolimus, temsirolimus or axitinib. However, the current evidence did not show the best treatment sequencing after first-line TKI failure. In patients with poor-risk clear-cell and non-clear cell mRCC, temsirolimus was the treatment option supported by phase III clinical trial. In addition, several new drugs, nowadays, are still being investigated and waiting for the result of phase II or III clinical trial, and this might change the standard therapy for mRCC in the future.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Inhibitors of the mammalian target of rapamycin (mTOR) are currently approved for the treatment of several cancers, and their use is associated with serious rash, which affects patient's quality of life and leads to undesirable dose reductions or interruptions. A meta-analysis of randomized controlled trials (RCTs) was performed to determine the overall risk of developing high-grade rash with mTOR inhibitors in cancer patients.. We searched the PubMed database and abstracts presented at the American Society of Clinical Oncology (ASCO) meetings up to December 2013 for relevant studies. Eligible studies included RCTs in which everolimus or temsirolimus was compared to controls in cancer patients. The summary incidence, relative risk (RR), and 95% confidence intervals (CI) were calculated using a random- or fixed-effects model depending on the heterogeneity of the included trials.. A total of 11 RCTs with 4752 patients (mTORs: 2725, controls: 2027) with a variety of solid tumors were included in the analysis. The incidences of all-grade (grade 1-4) and high-grade rash (grade 3-4) were 27.3% (95% CI 21.0-34.7%) and 1.0% (95% CI 0.6-1.4%), respectively. In comparison with controls, mTOR inhibitors significantly increased the risk for developing all-grade rash (RR = 3.55, 95% CI 3.0-4.20, p < 0.001) and high-grade rash (RR = 4.25, 95% CI 1.63-11.10, p = 0.003). The increased risk of high-grade rash did not vary significantly among different tumors (p = 0.91). There was no significant difference between everolimus and temsirolimus (p = 0.60). There was also no significant difference between mTOR inhibitors alone and in combination with other agents (p = 0.57).. Everolimus and temsirolimus significantly increased the risk of high-grade rash in cancer patients. Early recognition and appropriate treatment is recommended.

Topics: Drug Eruptions; Everolimus; Exanthema; Humans; Incidence; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Risk; Sirolimus; TOR Serine-Threonine Kinases

Two mTOR inhibitors, TEM and EVE, proved to be active in mRCC but have never been compared in a prospective trial. We aimed to compare their effectiveness in mRCC patients previously treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor, and performed a systematic review and meta-analysis of available evidence.. The MEDLINE/PubMed database was reviewed for studies that compared EVE with TEM from January 2006 to May 2014. Summary hazard ratio (HR) for overall survival (OS) and time to treatment failure (TTF) were calculated using random and fixed effects models depending on the heterogeneity of included studies. Statistical heterogeneity was assessed using the χ(2) test, and inconsistency was quantified with the I(2) statistic. Publication bias was evaluated using the Begg and Egger test.. Four studies were included in the meta-analysis; data of 937 patients were available: 545 received EVE and 392 TEM. Among the included patients, 863 [92%] were treated with sunitinib and 74 [8%] with pazopanib or sorafenib as first-line therapy. In the overall population, treatment with EVE decreased the risk of death by 26% over TEM (HR, 0.74; 95% confidence interval [CI], 0.59-0.93; P = .008). The TTF was evaluable in 692 patients; in this group, treatment with EVE decreased the risk of treatment failure by 30% (HR, 0.70; 95% CI, 0.56-0.88; P = .002). No significant heterogeneity or publication bias was found for OS and TTF.. In this analysis, we compared EVE with TEM as second-line therapy in mRCC, and report a significant difference between mTOR inhibitors, even if these results need to be confirmed in a prospective trial.

Topics: Carcinoma, Renal Cell; Databases, Bibliographic; Everolimus; Humans; Kidney Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome

Mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are approved for the treatment of a variety of malignancies. Fatigue has been described with these agents as a common side effect, although the overall incidence and risk remain unclear. We performed a meta-analysis to calculate the overall incidence of fatigue in cancer patients treated with everolimus and temsirolimus and to compare the differences in incidence with placebo. The electronic databases PubMed, Embase, Web of Science, and Cochrane databases were searched for studies to include in the meta-analysis. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with single drug everolimus or temsirolimus with toxicity data on fatigue. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included studies. A total of 9,760 patients with a variety of malignancies from 56 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade fatigue in cancer patients treated with mTOR inhibitor (everolimus or temsirolimus) were 45.4% (95% CI 36.9-55.8%) and 8.7% (95% CI 7.2-10.4%), respectively. The relative risks of fatigue of mTOR inhibitor compared to placebo were increased for all-grade (RR = 1.22, 95% CI 1.08-1.38, P = 0.002) and high-grade (RR = 1.82, 95% CI 1.24-2.69, P = 0.002) fatigue. The incidence of all-grade fatigue of patients treated with everolimus was higher than those with temsirolimus (RR = 1.85, 95% CI 1.71-2.01, P < 0.001). No significant difference was detected with between everolimus and temsirolimus in terms of high-grade fatigue (RR = 1.15, 95% CI 0.94-1.41, P = 0.18). Treatment with mTOR inhibitor, everolimus and temsirolimus, is associated with an increased incidence of fatigue in patients with cancer. Early detection and management of fatigue is needed.

Topics: Clinical Trials as Topic; Everolimus; Fatigue; Humans; Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Risk; Sirolimus; TOR Serine-Threonine Kinases

A deeper understanding of the role of autophagy, literally 'self-eating', in normal and cancer cell biology has emerged over the last few years. Autophagy serves as a vehicle for cells to respond to various stressors including genomic, hypoxic and nutrient stress, and to oppose mechanisms of 'programmed' cell death. Here, we review not only mechanisms of cell death and cell survival but also the early successes in applying autophagy inhibition strategies in solid tumors using the only currently available clinical inhibitor, oral hydroxychloroquine. In acute leukemia, currently available chemotherapy drugs promote cell death and demonstrate clinical benefit, but relapse and subsequent chemotherapy resistance is common. Increasing preclinical data suggest that autophagy is active in leukemia as a means of promoting cell survival in response to chemotherapy. We propose coupling autophagy inhibition strategies with current cytotoxic chemotherapy and discuss synergistic combinations of available anti-leukemic therapies with autophagy inhibition. Furthermore, novel autophagy inhibitors are in development and promise to provide new therapeutic opportunities for patients with leukemia.

Topics: Antineoplastic Agents; Autophagy; Boronic Acids; Bortezomib; Cell Survival; Clinical Trials as Topic; Drug Resistance, Neoplasm; Gene Expression; HMGB1 Protein; Humans; Hydroxychloroquine; Leukemia; Leukocytes; Lysosomes; Phagosomes; Pyrazines; Sirolimus

Disease progression despite existing endocrine therapies remains a major challenge to the effective management of hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)), advanced breast cancer. Recent advances in elucidating the molecular mechanisms of disease progression have identified the existence of adaptive "cross-talk" between the estrogen receptor (ER) and various growth factor receptor and intracellular signaling pathways, allowing breast cancer cells to escape the inhibitory effects of endocrine therapy. These findings provide the clinical rationale for enhancing or extending endocrine sensitivity by combining endocrine therapy with a targeted agent against a compensatory pathway. In BOLERO-2, adding the mTOR inhibitor everolimus to endocrine therapy significantly improved progression-free survival (PFS) in patients with HR(+) advanced breast cancer previously treated with nonsteroidal aromatase inhibitor therapy. Notably, PFS benefits were comparable in subgroup analyses of first- and later-line settings. These results contrast with those of the large first-line HORIZON study, wherein adding the mTOR inhibitor temsirolimus to endocrine therapy did not improve PFS. Therefore, it is unclear whether a targeted agent should only be combined with endocrine therapy to restore endocrine sensitivity or whether it may also prevent or delay resistance in hormone-sensitive advanced breast cancer. Numerous additional targeted agents are currently being evaluated in combination with endocrine therapies, including PI3K, cyclin-dependent kinase 4/6, SRC, and histone deacetylase inhibitors. Appropriate patient selection based on prior treatment history will become increasingly important in maximizing the incremental benefit derived from these new agents combined with existing endocrine therapies in HR(+) advanced breast cancer.

Topics: Anastrozole; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Bevacizumab; Biomarkers, Tumor; Breast Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Estradiol; Everolimus; Female; Fulvestrant; Humans; Molecular Targeted Therapy; Nitriles; Patient Selection; Postmenopause; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Sirolimus; Treatment Failure; Treatment Outcome; Triazoles

Inhibitors of the mammalian target of rapamycin (mTOR) pathway including everolimus and temsirolimus have been used extensively in cancer patients. Their use is associated with stomatitis, an adverse event resulting in morbidity and treatment interruptions or discontinuation. This study was conducted to determine the overall incidence and risk of stomatitis in cancer patients treated with the mTOR inhibitors by a meta-analysis of randomized controlled clinical trials (RCTs).. Databases from PubMed and abstracts presented at the American Society of Clinical Oncology annual meetings up to October 2013 were searched for relevant studies. Eligible studies included RCTs using everolimus and temsirolimus at approved doses in cancer patients. Summary incidences, relative risks (RR), and 95% confidence intervals (CI) were calculated using a random- or fixed-effects model depending on the heterogeneity of the included trials.. A total of 11 RCTs with 4,752 patients (mTORs: 2,725, controls: 2,027) with a variety of solid tumors were included in the analysis. The incidences of all-grade (grade 1-4) and high-grade stomatitis (grade 3-4) were 33.5% (95% CI: 21.9-47.6%) and 4.1% (95% CI: 2.6-6.3%), respectively. The incidence of high-grade stomatitis significantly varied with tumor types (p=.004), and mTOR inhibitors (temsirolimus vs. everolimus, p<.001). In comparison with controls, mTOR inhibitors significantly increased the risk for developing all-grade stomatitis (RR: 4.04, 95% CI: 3.13-5.22, p<.001) and high-grade stomatitis (RR: 8.84, 95% CI: 4.07-19.22, p<.001).. The mTOR inhibitors everolimus and temsirolimus significantly increased the risk of high-grade stomatitis in cancer patients. Efforts towards the prevention, treatment, and identification of individuals at risk may allow for improved quality of life and consistent dosing.

Topics: Everolimus; Humans; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

We performed a meta-analysis of fatigue associated with the use of everolimus, temsirolimus or ridaforolimus in patients with solid tumors. Eligible studies included randomized trials of patients with solid tumors on everolimus, temsirolimus or ridaforolimus describing events of fatigue. A total of 18 clinical trials including 8143 patients were considered eligible for the meta-analysis. On the basis of random-effects model, we found that the relative risk of all-grade and high-grade fatigue were 1.26 [95% CI: 1.09-1.46; p < 0.0001], 1.49 [95% CI: 0.99, 2.24; p = 0.05], respectively. On subgroup analysis, we cannot identify any difference between everolimus and temsirolimus in the risk of fatigue. Thus, our meta-analysis has demonstrated that regimens containing everolimus, temsirolimus or ridaforolimus for the treatment of solid tumors are associated with an increased risk of all-grade fatigue, whereas the risk of high-grade fatigue did not reach the threshold of statistical significance. Close clinical monitoring and pre-emptive treatment for fatigue are recommended.

Topics: Antineoplastic Agents; Everolimus; Fatigue; Humans; Neoplasms; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Risk; Sirolimus

Several 'lines of therapy' that utilize cytotoxic agents and are driven by platinum-free intervals are the current standard of care for patients with recurrent ovarian cancer. For patients with platinum-resistant disease, single agent chemotherapy (pegylated liposomal doxorubicin, topotecan, gemcitabine or weekly paclitaxel) is the standard of care. For patients with platinum-sensitive disease, combination chemotherapy (carboplatin plus paclitaxel, pegylated liposomal doxorubicin or gemcitabine) is the standard of care. In addition, antiangiogenic therapy using bevacizumab is an established option. Future directions could include 'lines of therapy' with biologic agents driven by specific biologic targets. Data from antiangiogenic agents (trebananib, pazopanib and cediranib), antifolate drugs (farletuzumab and vintafolide), poly(ADP-ribose) polymerase inhibitors (olaparib and veliparib), mTOR inhibitors (everolimus and temsirolimus) and immune editing agents (nivolumab) have been summarized in this review.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Carcinoma, Ovarian Epithelial; Deoxycytidine; Doxorubicin; Everolimus; Female; Folic Acid; Gemcitabine; Humans; Indazoles; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Nivolumab; Ovarian Neoplasms; Paclitaxel; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Glycols; Pyrimidines; Quinazolines; Recombinant Fusion Proteins; Sirolimus; Sulfonamides; Topotecan; TOR Serine-Threonine Kinases; Vinca Alkaloids

The authors performed a systematic review and meta-analysis of diarrhea and stomatitis associated with the use of everolimus, temsirolimus or ridaforolimus in patients with solid tumors.. Eligible studies included randomized trials of patients with solid tumors on everolimus, temsirolimus or ridaforolimus, describing the events of diarrhea and stomatitis.. After exclusion of ineligible studies, a total of 18 clinical trials including 8143 patients were considered eligible for the meta-analysis. The relative risk ratios of all-grade diarrhea and stomatitis were 1.94 (95% CI: 1.6-2.36; p < 0.00001) and 3.54 (95% CI: 2.59-4.84; p < 0.00001), respectively, while the relative risk ratios of high-grade diarrhea and stomatitis were 3.49 (95% CI: 2.39-5.09; p < 0.00001) and 6.98 (95% CI: 4.76-10.26; p < 0.00001), respectively. On subgroup analysis, there was no statistically significant difference between everolimus and temsirolimus in the risk of relevant adverse events.. This meta-analysis demonstrated that regimens containing everolimus, temsirolimus or ridaforolimus for the treatment of solid tumors are associated with a significantly increased risk of all-grade and high-grade diarrhea and stomatitis. Close clinical monitoring is required when administering these drugs.

Topics: Antineoplastic Agents; Diarrhea; Everolimus; Humans; Intestinal Mucosa; Mouth Mucosa; Neoplasms; Sirolimus; Stomatitis

The common dysregulation of the mTOR signaling pathway in tumor cells makes it a key target in oncotherapy. To better understand the effects of mTOR inhibitors, we analyzed 32 published clinical trials on solid tumors other than renal cell cancer, neuroendocrine tumors and metastatic breast cancer, for mTOR inhibitors are already approved by the US FDA to treat the three cancers. A lack of therapeutic effects was observed when mTOR inhibitors were used as a single agent. When combined with other agents, mTOR inhibitors still lacked sufficient clinical activity or just had minimal activity. More studies are required to better understand the clinically effects of mTOR inhibitors and the development of novel mTOR inhibitors is absolutely necessary.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials as Topic; Docetaxel; Erlotinib Hydrochloride; Everolimus; Gefitinib; Humans; Imatinib Mesylate; Neoplasms; Protein Kinase Inhibitors; Quinazolines; Signal Transduction; Sirolimus; Taxoids; TOR Serine-Threonine Kinases

A variety of therapeutic agents are currently available for the systemic treatment of metastatic renal cell carcinoma (mRCC). It was only when targeted treatment was developed in the past decade that a significant improvement was achieved in tumour therapy. This also led to the development of sequential treatment for mRCC.7 molecular targeted agents are available today (axitinib, bevacizumab/ IFNα, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus). Due to the individualisation of treatment it remains a challenge to choose the most appropriate drug in a given setting, with the choice being based on the knowledge of the relevant clinical data as well as individual patient parameters.During the recent past, efforts have been made to test different inhibitors or combinations without a major breakthrough. Instead, the development of novel specific immunotherapeutic approaches now heralds the next level of treatment in mRCC. The first significant trial results will be expected this year, and further trials for optimisation of treatment are warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Disease Progression; Everolimus; Humans; Imidazoles; Immunotherapy; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis

mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized.. PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated.. Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control.. The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control.

Topics: Antibiotics, Antineoplastic; Dyslipidemias; Everolimus; Humans; Hyperglycemia; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

Mammalian target of rapamycin (mTOR) inhibitors, temsirolimus and everolimus, are currently approved for the treatment of several malignancies. Hematological toxicities have been reported with these drugs, but overall incidence and relative risk remains undefined. We perform an up-to-date meta-analysis to determine the incidence and risk of hematologic toxicities associated with mTOR inhibitors.. Several databases were searched, including PubMed, Embase and Cochrane databases. Eligible studies included prospective phase II and III trials of temsirolimus and everolimus with adequate safety data profile reporting anemia, leucopenia, neutropenia or thrombocytopenia. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated by using either random effects or fixed effects models according to the heterogeneity of included studies.. A total of 5436 patients with a variety of solid tumors from 26 clinical trials were included for the meta-analysis. The overall incidences of mTOR inhibitor associated all-grade and high-grade hematologic toxicities were, respectively: anemia--38.8% and 7.5%; leucopenia--19.6% and 1.8%; neutropenia--14.9% and 5.6%; thrombocytopenia--33.1% and 3.6%. Compared to placebo/control arms, mTOR inhibitors were associated with a significantly increased risk of all-grade (RR 2.05, 95% CI: 1.52-2.77; p < 0.001) and high-grade anemia (RR 1.57, 95% CI: 1.20-2.05; p = 0.001), all-grade (RR 6.03, 95% CI: 2.76-13.14; p < 0.001) and high-grade thrombocytopenia (RR 2.73, 95% CI: 1.87-3.99; p < 0.001). Additionally, a non-significantly increased risk of all-grade leucopenia (RR 1.46, 95% CI: 0.66-3.23; p = 0.34) and neutropenia (RR 1.77, 95% CI: 0.80-3.93; p = 0.16) was observed in the mTOR inhibitor group, while the risk of high-grade leucopenia (RR 0.53, 95% CI: 0.31-0.90, p = 0.019) and neutropenia (RR 0.96, 95% CI: 0.62-1.51; p = 0.87) did not increase. Similar results were also observed in sub-group analysis according to mTOR inhibitor based regimens.. The use of mTOR inhibitors is associated with a significant increase in the risk of developing all-grade and high-grade anemia and thrombocytopenia compared with placebo/control arms.

Topics: Anemia; Antineoplastic Agents; Everolimus; Humans; Immunosuppressive Agents; Incidence; Neoplasms; Neutropenia; Protein Kinase Inhibitors; Risk; Sirolimus; Thrombocytopenia; TOR Serine-Threonine Kinases

Breast cancer cells can develop resistance to standard hormonal treatment and chemotherapy with the activation of the mTOR pathway; this is supported by results of preclinical and clinical studies. In clinical trials, the addition of everolimus to hormonal treatment or anti-HER2 treatment improved the outcomes of breast cancer patients. The aim of this review is to discuss the efficacy and safety data of everolimus in all categories of breast cancer in recent published studies.. Everolimus showed positive results in clinical studies. A literature search was made from PubMed, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts by using the following search key words: 'everolimus', 'RAD001', 'mTOR inhibitor', 'breast cancer' 'endocrine therapy resistance' and 'HER-2 targeted therapies'. The last search was on June 10, 2013. The most important limitation of our review is that most of the data on everolimus rely on phase I and II trials.. Preclinical studies showed that mTOR activation can be the responsible mechanism in all subgroups of breast cancer. Results of both the TAMRAD and BOLERO-2 studies have showed that mTOR inhibition in combination with endocrine therapy can be a new treatment strategy for MBC patients who are resistant to aromatase inhibitors. In the BOLERO-2 study, time to deterioration in health-related quality of life was also significantly higher in the everolimus and exemestane arm compared to the exemestane plus placebo arm. The recently completed BOLERO-3 study showed that mTOR inhibition in combination with trastuzumab plus vinorelbine treatment significantly improved PFS compared to trastuzumab plus vinorelbine alone in trastuzumab-resistant MBC patients.. Recent trials have shown that everolimus has produced promising anti-tumor activity in combination with trastuzumab in HER2-positive metastatic breast cancer and in combination with exemestane in patients with hormone-receptor-positive metastatic breast cancer who had recurrence or progression while receiving a nonsteroidal aromatase inhibitor. Results of ongoing studies with everolimus show evidence that using everolimus in earlier stages of the disease, namely in the adjuvant and neoadjuvant settings, could be benefical.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Disease-Free Survival; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Immunosuppressive Agents; Neoplasm Recurrence, Local; Paclitaxel; Receptor, ErbB-2; Sirolimus; TOR Serine-Threonine Kinases; Trastuzumab

Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer.. A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.. This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.. Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.

Topics: Ado-Trastuzumab Emtansine; Afatinib; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Everolimus; Female; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Maytansine; Molecular Targeted Therapy; Neoadjuvant Therapy; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinazolines; Quinolines; Receptor, ErbB-2; Sirolimus; TOR Serine-Threonine Kinases; Trastuzumab; Treatment Outcome; Up-Regulation

The historical treatment paradigm for metastatic renal cell carcinoma has focused on immunomodulatory agents, such as IFN-α and IL-2, which provide good clinical outcomes in only a subset of patients. The development of therapies that target the VEGF and mTOR pathways have significantly altered the treatment landscape for this disease, with novel inhibitors providing substantial improvements in progression-free and overall survival over previous standards of care. Despite these advances, toxicity from targeted therapy and the development of resistance results in disease progression. By contrast, vaccine-based immunotherapy represents a promising new approach for the treatment of patients with metastatic renal cell carcinoma; however, tumor-induced immunosuppression has limited the clinical efficacy of this modality until recently. Some evidence suggests that certain targeted therapies, such as sunitinib, may reduce this immunosuppression and enhance the tumor microenvironment to promote synergy with autologous dendritic cell vaccines.

Topics: Angiogenesis Inhibitors; Antigens, Neoplasm; Cancer Vaccines; Carcinoma, Renal Cell; Combined Modality Therapy; Dendritic Cells; Electroporation; Everolimus; Humans; Immunotherapy, Active; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Proteins; Phenylurea Compounds; Precision Medicine; Protein Kinase Inhibitors; Pyrroles; Quinolines; RNA, Neoplasm; Signal Transduction; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases; Tumor Microenvironment

The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. Unfortunately, a number of potential mechanisms that may lead to resistance to mTOR inhibitors have been proposed. In this paper, we discuss the mechanisms underlying resistance to mTOR inhibitors, which include the downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, the activation of hypoxia-inducible factor (HIF), the PIM kinase family, PTEN expression, elevated superoxide levels, stimulation of autophagy, immune cell response and ERK/MAPK, Notch and Aurora signaling pathways. Moreover, we present an updated analysis of clinical trials available on PubMed Central and www.clinicaltrials.gov, which were pertinent to the resistance to rapalogs. The new frontier of inhibiting the mTOR pathway is to identify agents targeting the feedback loops and cross talks with other pathways involved in the acquired resistance to mTOR inhibitors. The true goal will be to identify biomarkers predictive of sensitivity or resistance to efficiently develop novel agents with the aim to avoid toxicities and to better choose the active drug for the right patient.

Topics: Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The mechanistic (mammalian) targets of rapamycin (mTOR) inhibitors with known growth Inhibitory effect are currently in clinical trial for treatment of human cancer. The aim of this review is to present current incorporating these new drugs as single agents or in combination with other therapeutic modalities for treatment of gynecologic cancer.. A PubMed search was conducted on "mTOR inhibitors" and "human cancer". The relevant studies published between the year 2000 to present were reviewed. Those related to gynecologic cancer (cervical, endometrial and ovarian) were selected for this manuscript. The result of published data and their clinical application in gynecologic malignancies are presented.. mTOR is directly involved in many cell signaling pathways, and mTOR inhibitors have demonstrated anti-tumor activity against a variety of human malignancies, including gynecologic cancers. Combinations of mTOR inhibitors with other treatment modalities, e.g. cytotoxic chemotherapy, hormonal therapies, and other targeted molecular agents, have shown encouraging results particularly in endometrial and ovarian cancer.. Patients with advanced or recurrent gynecologic cancers who have failed initial treatment are need of new treatment modalities. There is strong evidence that mTOR inhibitors limit tumor proliferation and progression. The PI3k/AKT/mTOR pathway is often deregulated in gynecologic cancer. Patients with PIK3CA mutations are more responsive to PI3K/AKT/mTOR inhibitors than patients without these mutations. Routine screening for PIK3CA mutations warrants further investigation when PI3K/AKT/mTOR inhibitors are considered in treatment of patients with gynecologic cancer.

Topics: Antineoplastic Agents; Endometrial Neoplasms; Everolimus; Female; Humans; Ovarian Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Uterine Cervical Neoplasms

Most breast cancer (BC) patients have tumors that express hormone receptors (HRs). Although endocrine therapy, such as aromatase inhibitors, is very effective, most patients with metastatic HR-positive (HR(+)) BC become resistant to endocrine therapy at some point in their treatment and subsequently require chemotherapy. The PI3K/mTOR pathway is often upregulated in endocrine-resistant BC patients and, therefore, has been one of the targets for development of new agents. Recently, a Phase III trial (BOLERO-2) in aromatase inhibitor-resistant BC patients showed a significant improvement in time to progression with the combination of everolimus and exemestane compared with exemestane alone, confirming the importance of the PI3K/mTOR pathway in endocrine-resistant BC. Side effects from mTOR inhibitors are manageable, but early detection and proactive management are required to ensure patients' safety, compliance and continuity of treatment. Thus, mTOR inhibitors offer a new hope and promise for patients with HR(+) BC.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Everolimus; Female; Humans; Indoles; Purines; Sirolimus; TOR Serine-Threonine Kinases

Autophagy is the cellular process by which proteins, macromolecules, and organelles are targeted to and degraded by the lysosome. Given that neurodegenerative diseases involve the production of misfolded proteins that cannot be degraded by the protein quality-control systems of the cell, the autophagy pathway is now the focus of intense scrutiny, because autophagy is primarily responsible for maintaining normal cellular proteostasis in the central nervous system (CNS). Huntington's disease (HD) is an inherited CAG-polyglutamine repeat disorder, resulting from the production and accumulation of misfolded huntingtin (Htt) protein. HD shares key features with common neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) and, thus, belongs to a large class of disorders known as neurodegenerative proteinopathies. Multiple independent lines of research have documented alterations in autophagy function in HD, and numerous studies have demonstrated a potential role for autophagy modulation as a therapeutic intervention. In this review, we consider the evidence for autophagy dysfunction in HD, and delineate different targets and mechanistic pathways that might account for the autophagy abnormalities detected in HD. We assess the utility of autophagy modulation as a treatment modality in HD, and suggest guidelines and caveats for future therapy development directed at the autophagy pathway in HD and related disorders.

Topics: Animals; Autophagy; Endoplasmic Reticulum Stress; Humans; Huntingtin Protein; Huntington Disease; Nerve Tissue Proteins; Sirolimus; Trehalose

Synovial sarcoma is part of soft tissue sarcomas, an uncommon group of malignant tumors of mesenchymal origin. Unfortunately, a very limited number of useful drugs are active for most advanced synovial sarcoma. These tumors showed VEGF expression, and elevated serum VEGF levels correlate with higher histologic tumor grade. Inhibition of VEGFR was associated with tumor activity in preclinical models of synovial sarcoma and drugs such as sorafenib, pazopanib and bevacizumab have been employed in synovial sarcoma in monotherapy and in combination with chemotherapy. Other targets such as EGFR, HER2, IGFR-1R and mTOR have been exploited, but their inhibition by drugs such as gefitinib, trastuzumab, figitumumab, and temsirolimus, has not resulted in meaningful activity. Newer approaches include CXCR4 inhibition, immune-based therapies (NY-ESO-1), targeting epigenetic misregulation with HDAC inhibitors and targeting developmental pathways such Notch and Hedgehog. This review will summarize achievements and pitfalls of drugs against emerging therapeutic targets for synovial sarcoma.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bevacizumab; Everolimus; Humans; Indazoles; Indoles; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Sarcoma, Synovial; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases

Temsirolimus, an ester of sirolimus (rapamycin), selectively inhibits the kinase mammalian target of rapamycin (mTOR) and consequently blocks the translation of cell cycle regulatory proteins and prevents overexpression of angiogenic growth factors. It has been found to have antitumour activity in patients with relapsed or refractory mantle cell lymphoma (MCL). In addition, patients with advanced renal cell carcinoma (RCC) and a poor prognosis who received a once-weekly intravenous (IV) infusion of temsirolimus 25 mg experienced significant survival benefits compared with patients receiving standard interferon-α (IFN-α) therapy in a large phase III clinical study. In this study, median overall survival was 10.9 versus 7.3 months and objective response rates were 8.6% in temsirolimus recipients versus 4.8% IFN-α recipient group. Temsirolimus monotherapy recipients experienced significantly fewer grade 3 or 4 adverse events and had fewer withdrawals for adverse events than patients receiving IFN-α. The role of temsirolimus in sequential and combination therapy is yet to be found.

Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Since 2006, new treatments as targeted therapies (anti angiogenic and mTOR inhibitors) are prescribed in renal cell cancer. Toxicity of these treatments is well known by clinicians. Occurrence of these side effects has been associated with anti tumoral efficacy. High blood pressure, hypothyroïdie and hand foot syndrome were reported to be predictive of anti tumoral response. Fatigue and hyponatremia are still largely discussed. Moreover, non infectious pneumonia, which frequently occurs with mTOR inhibitors, is associated with clinical benefit. The main objective of treatment of advanced kidney cancer, specially renal cell cancer, is obtaining clinical benefit (stabilization and response) with a chronic evolution of the disease. This prolong exposure to drugs, according to their toxicity profile, often contributes to dose reduction, moreover interruption of treatment, potentially associated with a loss of control of disease. Thus, the adverse effects, described hereby, may be considered as « positive events », predicting efficacy, and thus looked for… Moreover, the sequential approach, with new drugs, emphasizes the need of defining the optimal sequence. Thus, because of the lack of molecular biomarkers to date, this predictives secondary effects may help for selecting the therapeutic strategy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Asthenia; Carcinoma, Renal Cell; Everolimus; Hand-Foot Syndrome; Humans; Hypertension; Hypothyroidism; Kidney Neoplasms; Molecular Targeted Therapy; Prognosis; Sirolimus; Treatment Outcome

Prognosis of metastatic renal cell carcinoma (mRCC) has markedly improved in the recent years. Several factors such as precocious diagnosis, better supportive care, and an increased number of targeted therapies are responsible for this progress. From 2006 to date, 7 drugs have been approved for treatment of mRCC, and among these only 2 are recommended for the second line of therapy with grade 1 evidence. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors are the strategies with more evidence, but no comparative studies are available and what is the best second line remains an open issue. Herein, we review the available evidence on the second-line treatment focusing mainly on prospective studies. We identify a special population of patients in whom more evidence is available, and we propose a possible strategy for the management of progressed mRCC and for primary resistant lesions as well as for patients who need a rapid response in lesions. In the majority of patients, several factors should be considered: toxicity reported during first-line therapy, performance status, the absence of correlation between the length of first-line therapy and the probability to respond to second-line therapy, and the lack of comparative trials between mTOR inhibitors and TKI. When an mTOR inhibitor is selected, everolimus must be preferred, although in the RECORD1 trial only the increase in progression-free survival has been reported and the increase in terms of overall survival has not been reached. When another TKI is the choice, there are no strong pieces of evidence that favor the use of a defined molecule. In every case, we recommend to start the selected targeted agents at standard dosage and to pursue therapy as long as possible because the control of disease should be the primary endpoint for the management of mRCC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrroles; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Treatment Failure; Vascular Endothelial Growth Factor Receptor-2

Inhibition of the mammalian target of rapamycin (mTOR) is an established treatment for multiple malignancies. We carried out an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors.. PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to approved mTOR inhibitors (everolimus and temsirolimus) and reported on patients with cancer, randomized design and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.. In all, 3193 patients from eight randomized, controlled trials (RCTs) were included, 2236 from everolimus trials and 957 from temsirolimus trials. The relative risk (RR) of FAEs related to mTOR inhibitors use was 2.20 (95% CI, 1.25-3.90; P = 0.006) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types [renal cell carcinoma (RCC) versus non-RCC]. No evidence of publication bias was observed.. The use of mTOR inhibitors is associated with a small but higher risk of FAEs compared to control patients. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Protein Kinase Inhibitors; Risk; Sirolimus; TOR Serine-Threonine Kinases

Most patients with mantle cell lymphoma (MCL) relapse within a few years of treatment. Conventional agents provide little benefit, thus identification of new therapies is critical to improve patient outcomes. Temsirolimus, an inhibitor of mammalian target of rapamycin, is an effective, well-tolerated option authorized in Europe for treatment of patients with relapsed/refractory MCL. Intravenous temsirolimus has been extensively studied in MCL and has consistently demonstrated single-agent antitumor activity. In the pivotal phase III trial, treatment with temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly (175/75 mg) resulted in significant improvements in progression-free survival (P = .0009) and objective response rate (P = .002) vs. investigator's choice of therapy. Hematologic toxicities (thrombocytopenia, neutropenia) were the principal grade 3/4 adverse events associated with temsirolimus 175/75 mg. Other toxicities included increases in serum cholesterol and triglycerides, hyperglycemia, fatigue, and dyspnea. Overall, the safety profile of temsirolimus is acceptable in this setting, and most toxicities are manageable with dose modification or medical intervention. Clinical studies of temsirolimus in relapsed or refractory MCL patients aim to clarify the optimal treatment schedule and to assess rational combinations with other therapeutic agents, such as rituximab or chemotherapy. Practical considerations are discussed for the clinical use of temsirolimus in patients with MCL.

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Recurrence; Sirolimus

Tyrosine kinase inhibitors have revolutionized the treatment of metastatic renal cell carcinoma (RCC). Drugs such as sorafenib, sunitinib and pazopanib act on the VEGF receptor pathway, but they can also inhibit other kinases, resulting in off-target toxicities. Tivozanib was developed due to its potency and selectivity against VEGF receptors 1-3. It has a favorable pharmacokinetic profile after oral administration and a long plasma half-life. In the Phase III TIVO-1 trial, it demonstrated a higher response rate and longer progression-free survival than sorafenib with a better side-effect profile. It is currently awaiting approval to be used in the first-line treatment of metastatic RCC. An early-phase trial has also shown its tolerability at full dose when given with the mTOR inhibitor temsirolimus, suggesting its potential in combination treatment. This article examines tivozanib from its laboratory to clinical development, as well as its relevance and future role in the treatment of RCC in the era of the tyrosine kinase inhibitors.

Topics: Animals; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Kidney Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Receptors, Vascular Endothelial Growth Factor; Sirolimus

With seven agents approved for renal cell carcinoma within the past few years, there has undoubtedly been progress in treating this disease. However, patients with poor-risk features remain a challenging and difficult-to-treat population, with the mTOR inhibitor, temsirolimus, the only agent approved in the first-line setting. Phase III trial data are still lacking VEGF-pathway inhibitors in patients with poor prognostic features. Poor-risk patients need to be considered as a heterogeneous population. Further understanding of biomarkers can lead to a better selection of patients who may benefit the most from treatment and improvements in prognosis. The presence of poor Karnofsky scores and liver or CNS disease may affect the outcome of these patients much more than other identified factors. This consideration may provide the rationale to further stratify poor-risk patients further subgroups destined to receive either cure or palliation.

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Palliative Care; Protein Kinase Inhibitors; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases

Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined.. We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.. A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3-2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21-8.67, p = 0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed.. With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

Topics: Antineoplastic Agents; Cause of Death; Everolimus; Humans; Incidence; Neoplasms; Protein Kinase Inhibitors; Risk; Sirolimus; TOR Serine-Threonine Kinases

With the introduction of multiple new targeted agents for the treatment of metastatic renal cell carcinoma, specific attention must be given to toxicities induced by these agents.. Agents with activity on the same target can have different toxicities, which might lead the clinician to select or individualize therapies. However, some data also support the concept of maximal tolerated dose as a marker of efficacy. Specific elements of these data are summarized and discussed in the paper.. Toxicity management is pivotal in individualized cancer care. This papers outlines some of the principles related to disease and toxicity management.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; Sunitinib

The introduction of therapy targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapomycin (mTOR) has significantly improved the outcome of patients with metastatic renal cancer. In this article a comprehensive overview of treatment choices for previously untreated patients with metastatic disease is given. Both established and emerging therapeutic options are discussed, as are prognostic factors predicting outcome.

Topics: Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib

An impressive variety of targeted therapies has been approved for the treatment of metastatic renal cell carcinoma (mRCC). Despite promising progress, there are still unmet clinical needs. The optimal sequence of these agents in the therapeutic setting has not yet been determined. Most available data address first- and second-line therapy of clear cell RCC. The mTOR inhibitor temsirolimus has been approved for first-line treatment of mRCC, and there are new data addressing the use of temsirolimus in later therapeutic lines. Temsirolimus has discerning features compared with other currently registered drugs, such as its intravenous administration route-providing predictable bioavailability and adherence to treatment-and potential benefit in nonclear cell histologies. Here, we review the available literature on temsirolimus, with reference to data also available for everolimus, to determine its clinical potential in mRCC.

Topics: Carcinoma, Renal Cell; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

To describe drugs used in renal cell carcinoma.. Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies websites (HAS and ANSM).. Since 2007, a total of three different therapeutic classes in the management of metastatic renal cell carcinoma are available. These three classes are tyrosine kinase inhibitors with sunitinib and sorafenib, the anti-VEGF antibodies (bevacizumab which is associated with alpha interferon in the treatment of advanced kidney cancer) and mTOR inhibitors with temsirolimus and everolimus. These targeted therapies are a major progress in the treatment of patients with metastatic kidney cancer. The side effects encountered with these molecules are numerous but serious side effects are less than 5% of all reported side effects.. A better understanding of molecular mechanisms has enabled the development of new therapies for the treatment of metastatic renal cell carcinoma. In the future, a personalized approach taking into account the biology of each tumor could be created to provide a more targeted treatment.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Immunotherapy; Indoles; Interferon alpha-2; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Recombinant Proteins; Sirolimus; Societies, Medical; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Advancing age represents the primary risk factor for renal tumors. Despite findings on the inhibition of angiogenesis that have led to six new drugs to treat metastatic renal cell carcinoma, elderly patients have not been fully represented in clinical trials. In addition, current opinions regarding nephrectomy in elderly patients are conflicting. Available data refer to the efficacy and safety of sorafenib, sunitinib, everolimus, bevacizumab and temsirolimus in patients aged 65 years and older; safety and efficacy data are available only for sunitinib, sorafenib,and everolimus in patients aged 70 years and older and only sorafenib has safety data for patients aged 75 years and older. A different approach based on evaluating comorbidities at baseline, risk of drug interactions and the impact of antitumor treatment in patients with polytherapy regimen is discussed. A decision-making algorithm is proposed to facilitate the selection of the best therapy for kidney tumors for a specific elderly patient profile.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Autophagy is a degradation pathway for long-lived cytoplasmic proteins, protein complexes, or damaged organelles. The accumulation and aggregation of misfolded proteins are hallmarks of several neurodegenerative diseases. Many researchers have reported that autophagy degrades disease-causing misfolded and aggregated proteins, including mutant huntingtin (Htt) in Huntington's disease, mutant synuclein in familial Parkingson's disease, mutant Cu, Zn-Superoxide dismutase (SOD1) in familial amyotrophic lateral sclerosis. In this review, we will bring up new evidence to elucidate the involvement of autophagy in degradation of mutant Htt, discuss the mechanisms regulating the degradation of mutant Htt by autophagy and the therapeutic effects of drugs that enhance autophagy to improve clearance of mutant Htt. We propose that enhancement of autophagy by drugs may be a strategy to treat or retard progression of Huntington's disease.

Topics: Autophagy; Carbamazepine; Humans; Huntingtin Protein; Huntington Disease; Lithium; Mutant Proteins; Nerve Tissue Proteins; Oxazoles; Peptides; Rilmenidine; Sirolimus; Trehalose; Trinucleotide Repeat Expansion; Valproic Acid

Mammalian target of rapamycin (mTOR) is a crucial mediator of tumor progression and may be a promising target in a significant proportion of patients with breast cancer. More specifically, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway plays a critical role in multiple cellular functions including metabolism, proliferation, growth and survival. This pathway is higly active in many types of cancer and is linked to resistance to many types of therapy. Direct blockade of the mTOR pathway is a new area in breast cancer therapy, with the potential to modulate growth factor- and estrogen-dependent and estrogen-independent pathways, which contribute to the pathogenesis and progression of tumors. Thus, inhibitors of mTOR are of interest as potential therapeutic agents for patients with breast cancer, everolimus and temsirolimus being the main representatives of this category. This review of the literature analyzes the available data emerging from trials and evaluates the efficacy and safety of mTOR inhibitors in all subtypes of breast cancer.

Topics: Breast Neoplasms; Clinical Trials as Topic; Drug Resistance, Neoplasm; Estrogens; Everolimus; Female; Humans; Molecular Targeted Therapy; Neoplasms, Hormone-Dependent; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, ErbB-2; Sirolimus; TOR Serine-Threonine Kinases

Identification of the role of biological pathways in metastatic renal cell carcinoma (mRCC) has led to the development of targeted agents for its treatment, in particular those that inhibit the vascular endothelial growth factor pathway, and inhibitors of mammalian target of rapamycin (mTOR). mTOR is central to signalling pathways that regulate cellular growth, proliferation and survival, and this paper focuses on the two currently licensed mTOR inhibitors, temsirolimus and everolimus. These agents are administered via different routes (intravenously and orally, respectively), and this has an impact on their pharmacokinetics; intravenous temsirolimus is not affected by variable absorption in the gastrointestinal tract or by food intake, unlike the orally administered mTOR inhibitor everolimus. Temsirolimus is administered weekly, whereas everolimus is currently approved for daily dosing. In general, intravenous administration is likely to ensure better control of plasma drug concentrations, greater treatment adherence, and more regular monitoring of toxicity and therapeutic response, although it can be uncomfortable and inconvenient for patients. Oral administration is preferred by patients for its convenience, but can be associated with suboptimal adherence to treatment, and poor and variable bioavailability. Temsirolimus and everolimus have both been associated with improved outcomes in patients with mRCC but, as reviewed in this paper, the pharmacokinetic characteristics of these agents differ in many respects.

Topics: Administration, Intravenous; Administration, Oral; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Neoplasm Metastasis; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Temsirolimus (Torisel) is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). The recommended dosage in this indication (175 mg once weekly for 3 weeks and then 75 mg once weekly as maintenance) is higher than that for renal cell carcinoma; thus, the safety profile is quite different in the two indications. The aim of this review is to examine safety data for temsirolimus in MCL and provide guidance on the incidence and management of adverse events. Medline and EMBASE searches using the search terms 'temsirolimus' and 'mantle cell lymphoma'.. Four main published phase II-III clinical studies of temsirolimus in MCL were identified. Many adverse events are class-effect toxicities of mTOR inhibitors but, for others, often an accurate relationship with temsirolimus is difficult to assess with certainty. Haematological adverse events are the most frequently reported, but these are generally successfully managed by dose reductions or treatment delay. Gastrointestinal toxicity, especially diarrhoea, is a frequent and common adverse effect, but the incidence of grade 3-4 events is low. Other non-haematological toxicities include stomatological/dermatological and endocrinological adverse events. Incidence of these adverse events can be reduced by careful management and/or prevention. Grade 3 or higher pneumonitis, a known mTOR inhibitor-associated toxicity, was rarely reported in this indication, but the incidence was higher when temsirolimus was administered in combination with rituximab. Other adverse events include fatigue/asthenia, infection, hypersensitivity and extravasation. Sexual disorders, foetal malformations and psychiatric disorders are rarely reported.. Most temsirolimus-associated adverse events in patients with relapsed/refractory MCL are manageable, often without impacting administration of temsirolimus.

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Lymphoma, Mantle-Cell; Sirolimus

PI3K/AKT/mTOR pathway is an intracellular signalling pathway composed of different kinases. Many protein mutations are described in that pathway, and are responsible of dysregulation of cell growth, proliferation, survival and angiogenesis. Rapamycin is an antibiotic inhibiting mTOR. Different analogs of rapamycin are developed or being developed in antitumoral therapy, in which temsirolimus, everolimus and deforolimus, demonstrated antitumoral activity in renal cancer and mantle cell lymphoma, and many clinical trials are in progress in other tumors. In the future, predictive factors of response need to be identified; patient selection and associations with chemotherapy or with other targeted therapies should be explored.

Topics: Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Lymphoma, Mantle-Cell; Neovascularization, Pathologic; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

We conducted a systematic review of the literature and performed a meta-analysis to determine the risk of developing skin rash and stomatitis among patients receiving temsirolimus.. Databases from PubMed and Web of Science from January, 1998 until June, 2011 and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2011 were searched to identify relevant studies. The incidence and relative risk (RR) of skin rash and stomatitis were calculated using random-effects or fixed-effects model depending on the heterogeneity of included studies.. A total of 779 patients from 10 clinical trials were included in this analysis. The overall incidence of all-grade rash was 45.8% (95% confidence interval (CI): 35.6-56.3%), with a RR of 7.6 (95%CI: 4.4-13.3; p<0.001). The overall incidence of high-grade rash was 3.3% (95%CI: 1.9-5.6%), with a RR of 13.70 (95%CI: 0.82-227.50, p=0.07). The overall incidence of all-grade stomatitis was 44.3% (CI: 32.1-57.1%), with a RR of 11.10, 95%CI: 5.60-22.00; p<0.001). The overall incidence of high-grade stomatitis was 3.2% (95%CI: 1.9-5.4%), with a RR of 13.2 (95%CI: 0.80-218.50, p=0.07).. There is a significant risk of developing skin rash and stomatitis in cancer patients receiving temsirolimus. The risk is independent of underlying tumour. Adequate monitoring and early intervention are recommended to prevent debilitating toxicity and suboptimal dosing.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Exanthema; Humans; Incidence; Protein Kinase Inhibitors; Risk Factors; Sirolimus; Stomatitis

With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC-sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC.

Topics: Anorexia; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cardiovascular System; Drug Eruptions; Europe; Everolimus; Evidence-Based Medicine; Gastrointestinal Tract; Humans; Hypothyroidism; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pneumonia; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Weight Loss; Wound Healing

Head and neck squamous cell carcinomas (HNSCC) represent 6% of all cancers diagnosed each year in the United States, affecting approximately 43,000 new patients and resulting in approximately 12,000 deaths. Currently, three main rapalogs exist for the treatment of cancer: CCI-779 (temsirolimus), RAD001 (everolimus), and AP235373 (deforolimus). Clinicians managing HNSCC need to be aware of the three rapalogs. Extensive evidence has shown rapamycin-analogs to be effective agents in the treatment of a number of solid tumors. While extensive preclinical data suggests that HNSCC would be an appropriate tumor type to benefit from inhibition of the mTOR pathway, limited clinical data is yet available to support this. Numerous phase II trials evaluating mTOR inhibitors for use in HNSCC are currently recruiting patients.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Clinical Trials as Topic; Everolimus; Female; Head and Neck Neoplasms; Humans; Male; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; United States

Ovarian cancer is the most lethal gynecologic cancer. Traditional therapies have included surgical management and cytotoxic chemotherapy; however, treatment paradigms continue to shift from empiric cytotoxic chemotherapy to more individualized treatment. Recent research efforts have focused on determining and targeting the molecular biological mechanisms of ovarian cancer in an attempt to develop novel therapeutic modalities with the ultimate goal of improving outcome while limiting toxicity. This chapter reviews progress in the development of novel therapies directed at major pathways implicated in ovarian tumorigenesis including angiogenesis, PARP inhibition, signal transduction, antifolate therapies, death receptor-mediated therapies, histone deacetylase inhibition, immunotherapeutics, and oncolytics.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Bevacizumab; CA-125 Antigen; Clinical Trials as Topic; Docetaxel; Enzyme Inhibitors; Female; Folate Receptor 1; Genes, BRCA1; Genes, BRCA2; Genetic Therapy; Histone Deacetylase Inhibitors; Humans; Insulin-Like Growth Factor Binding Protein 1; Interleukin-12; Mutation; Oncogene Protein v-akt; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Receptors, TNF-Related Apoptosis-Inducing Ligand; Sirolimus; Taxoids; Vascular Endothelial Growth Factor A

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-Kinase (PI3K)/AKT signalling pathway with a central role in the control of cell growth, survival and angiogenesis. Multiple and frequent dysregulations of this pathway in human tumors make it a central target in the development of new anticancer treatments.. To review the most significant data on mTOR pathway, role of mTOR inhibitors in cancer treatment, preclinical and clinical data of the three first generation mTOR inhibitors (temsirolimus, everolimus and deferolimus), rationales, preclinical and clinical data of second generation mTOR inhibitors.. Review of published literature on mTOR and related pathways, rapalogs and novel mTOR inhibitors.. Temsirolimus and everolimus have been approved for the treatment of metastatic Renal Cell Carcinoma (RCC), temsirolimus also for Mantle Cell Lymphoma (MCL) and everolimus will be approved for pancreatic neuroendocrine tumors; all three rapalogs are currently evaluated in phase III studies in several tumors. Only limited published data are available on new mTOR inhibitors; however, in vitro and in vivo in preclinical studies they have shown a significant antiproliferative activity against a broad panel of tumors and a favourable safety profile, with disease stabilization or even tumor regression, either as single agent or in combination.

Topics: Everolimus; Humans; Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Tuberous sclerosis complex is an autosomal dominant disease, with variable expressivity and multisystemic involvement, which is characterised by the growth of benign tumours called hamartomas. The organs that are most commonly affected are the brain, skin, kidneys, eyes, heart and lungs. Of all the children with this disease, 85% present neurological manifestations that, due to their severity, are the main cause of morbidity and mortality. The most significant neurological manifestations are epilepsy, autism spectrum disorders and mental retardation. It has been shown that in tuberous sclerosis complex the genes TSC1 and TSC2 alter the mTOR enzyme cascade, which sets off inhibition of this pathway. The possibility of resorting to treatments applied at the origin, thus inhibiting this pathway, is currently being evaluated.

Topics: Anticonvulsants; Astrocytoma; Autistic Disorder; Brain Diseases; Brain Neoplasms; Drug Design; Epilepsy; Everolimus; Glioma, Subependymal; Hamartoma; Humans; Intellectual Disability; Learning Disabilities; Molecular Targeted Therapy; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Temsirolimus belongs to the mammalian target of rapamycin (mTOR) inhibitors, targeted therapies for which indications are booming in oncology. While their tolerance is usually good, mucocutaneous toxicity is the most common, including stomatitis, rashes, edemas, pruritus, dry skin and nail disorders. The latter are common in clinical practice but have not yet been well characterized. We report 2 cases of patients who developed, after 6-7 months with temsirolimus, a dystrophy of the 20 nails with fragility, distal onycholysis, yellow discoloration, associated in 1 case with painful paronychia. Topical steroids improved the paronychia, without changing the nail dystrophy. To our knowledge, the occurrence of yellow nail discoloration with temsirolimus has never been reported before. We review the cutaneous and mucosal toxicities induced by temsirolimus and everolimus, two mTOR inhibitors used as anticancer agents and by their parent molecule sirolimus.

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Middle Aged; Nail Diseases; Sirolimus; Steroids; TOR Serine-Threonine Kinases; Treatment Outcome

The study was carried out to evaluate the effectiveness, toxicity and optimal duration of neoadjuvant therapy for patients with organ-confined or locally advanced renal cell carcinoma in the era of targeted agents. A literature review was carried out using Medline/Pubmed articles, as well as congress reports from the last five American Society of Clinical Oncology, American Urological Association and European Association of Urology Annual Meetings. Neoadjuvant targeted therapy is feasible and shows toxicity similar to that seen in a palliative setting. Most studies recommend an application for 2-4 months. The current data situation is best for sunitinib. Surgery can apparently be carried out the day right after discontinuing the drug. However, even sunitinib leads to only a mean 10% decrease in primary tumor size, and one-quarter to one-fifth of all patients show local tumor progression during treatment. Few patients (approximately 12%) with a vena cava tumor thrombus achieve a significant decrease in its level under neoadjuvant therapy; here too, progression is observed in a significant number of cases. Even the new targeted agents show limited effectiveness in achieving relevant remissions of the primary tumor. Furthermore, tumor progression is seen in a significant percentage of patients during neoadjuvant therapy. Thus, even today in the era of targeted agents, a neoadjuvant approach should only be made in patients with localized or locally advanced renal cell carcinoma, which primarily seem to be absolutely inaccessible by (partial) nephrectomy.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Vena Cava, Inferior

Prognosis of patients with renal carcinoma has improved since the advent of targeted therapies. These last years, due to the improvement of patients overall survival, the incidence of brain metastasis among renal carcinoma patients has increased. This worsens the prognosis of patients. The present revue aims to do a point on treatment of brain metastasis from renal carcinoma. It will address both locoregional (surgery, radiotherapy and stereotactic radiosurgery) and systemic (targeted therapies) treatments.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Brain Neoplasms; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Prognosis; Radiosurgery; Receptor Protein-Tyrosine Kinases; Sirolimus

Despite the success of modern therapy for Hodgkin lymphoma (HL), about 15 % of patients will fail both first-line and second-line therapy and treatment options for these patients are limited. New agents are needed to improve the outcome for relapsed or refractory HL and to improve the toxicity of current front-line regimens. Brentuximab vedotin (BV) was recently approved for HL and is likely to have a tremendous impact on the current treatment paradigm for HL. Additional agents that have demonstrated activity in HL include histone deacetylase inhibitors, such as panobinostat, entinostat, and mocetinostat, PI3-kinase/Akt/Mtor pathway inhibitors, such as everolimus, as well as lenalidomide and bendamustine. Studies evaluating these agents alone or in combination with either chemotherapy or other targeted agents are ongoing. Current challenges in HL research include identifying the most appropriate drug combinations of new and old drugs and identifying predictors of response to the new targeted agents.

Topics: Antineoplastic Agents; Bendamustine Hydrochloride; Brentuximab Vedotin; Everolimus; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Immunoconjugates; Lenalidomide; Nitrogen Mustard Compounds; Protein Kinase Inhibitors; Sirolimus; Thalidomide

Non-clear cell renal cell carcinomas (nccRCCs) comprise a heterogenous and poorly characterized group of tumor types for which few treatments have been approved. Although targeted therapies have become the cornerstones of systemic treatment for metastatic renal cell carcinoma, patients with nccRCC have been excluded from many pivotal clinical trials. As such, robust clinical evidence supporting the use of these agents in patients with nccRCC is lacking. Here, we review the disparate nccRCC subtypes, the criteria for diagnosis, and the prognoses associated with each subtype, in addition to evaluating the potential use of mammalian target of rapamycin (mTOR) inhibitors in treating patients with nccRCC. Both genetic analyses and preclinical research indicate a central role for mTOR in nccRCC; a therapy that targets this ubiquitous regulator of cellular signaling could prove efficacious across various tumor subtypes. Results from recent studies exploring targeted therapies as both monotherapy and combination therapy have provided early indications of efficacy in patients with nccRCC. Exploratory analyses support further research with the mTOR inhibitors everolimus and temsirolimus in patients with nccRCC. Current clinical practice guidelines support the use of mTOR inhibitors in patients with nccRCC; however, these recommendations are based on low levels of evidence. Further results from randomized, controlled clinical trials are needed to determine the optimal choice of therapy for patients with nccRCC. Results from ongoing clinical trials of mTOR inhibitors and other agents in nccRCC, as well as their impact on the nccRCC treatment paradigm, are eagerly awaited.

Topics: Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The vascular endothelial growth factor (VEGF) pathway and the mammalian Target of Rapamycin (mTOR) represent the most frequently exploited targets in renal cell carcinoma (RCC). Temsirolimus is an inhibitor of mTOR, and is a unique ester derivative of sirolimus, a macrocyclic lactone, with improved pharmaceutical properties, including stability and solubility. Temsirolimus binds to the cytoplasmic protein FKBP-12, and the complex binds and inhibits mTOR.. This review summarizes the clinical findings and safety of temsirolimus in RCC patients.. A Phase III clinical trial has demonstrated that temsirolimus has statistically significant advantages over treatment with IFN-α in RCC patients with poor prognosis, in terms of OS (overall survival), PFS (progression-free survival), and tumor response. Median OS was improved 49% compared to IFN-α, and median PFS was approximately doubled. It is now considered the standard for RCC patients with poor prognostic features. The possibility that this agent is useful in metastatic non-clear cell carcinoma patients has also been suggested by a subset analysis of the pivotal Phase III trial. Studies in untreated favorable and intermediate risk clear cell and refractory mRCC patients are required.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Evaluation; Drug Monitoring; Humans; Kidney Neoplasms; Product Surveillance, Postmarketing; Prognosis; Protein Kinase Inhibitors; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Tumor Burden

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumors, whose incidence and prevalence are increasing. The clinical behavior of NEN is variable, ranging from well-differentiated slow growing tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. The term carcinoid is commonly used for the more benign variants of these neoplasms. Most frequently, carcinoids have their origin in the small intestine, followed by in the lung and other sites. Some of these tumors are associated with the carcinoid syndrome. The use of somatostatin analogs has revolutionized the clinical management of patients with carcinoids. However, although symptomatic relief and stabilization of tumor growth for various periods of time are observed in many patients treated with somatostatin analogs, tumor regression is rare. Currently, there is no other powerful antiproliferative agent available for carcinoids. Mammalian target of rapamycin (mTOR), a main protein kinase in the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway, is an important intracellular mediator involved in multiple cellular functions including proliferation, differentiation, apoptosis, tumorigenesis, and angiogenesis. Alterations of the normal activity of mTOR and of mTOR-related kinases in this pathway have been found in a diversity of human tumors, including NEN; therefore, mTOR pathway represents an attractive target for new anticancer therapies. While mTOR inhibitors, such as everolimus, are established therapy in pancreatic NEN, results from recent clinical trials indicate that mTOR inhibitors may be also of value in the management of carcinoids. However, further clinical trials will have to confirm efficacy and elucidate, in which subtypes and in which setting, these drugs might be most usefully applied.

Topics: Antineoplastic Agents; Carcinoid Tumor; Cell Differentiation; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Medical Oncology; Models, Biological; Neuroendocrine Tumors; Phosphatidylinositol 3-Kinases; Signal Transduction; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases; Treatment Outcome

mTOR inhibitors are currently used in the treatment of solid malignancies. Since their approval, several cases of pulmonary toxicity (PT) have been described. This analysis aims to report the incidence and the risk of PT in published randomized controlled trials.. PubMed and Scopus were reviewed for phase II-III randomized controlled trials with temsirolimus and everolimus. The characteristic of each study and incidence of all- and high-grades PT were collected.. A total of 2233 patients were available for meta-analysis: 989 had breast cancer, 833 had neuroendocrine tumor and 411 had metastatic renal cell carcinoma. In patients taking mTOR inhibitors, the incidence of all- and high-grades PT was 10.4% and 2.4%, respectively. Compared to controls, the relative risk for all- and high-grades PT was 31- and 8.8-folds, respectively. No significant heterogeneity was observed between the studies. Not any relationship was found between the incidence of lung metastases, treatment exposure and the incidence of PT.. The high grade PT is a rare event and 10% of patients may experience mild grade toxicity with a worsening of quality of life and interruption of therapy in some cases. We recommend monitoring of PT in patients treated with mTOR inhibitors.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Humans; Incidence; Kidney Neoplasms; Lung; Neoplasms; Neuroendocrine Tumors; Pneumonia; Randomized Controlled Trials as Topic; Respiratory Function Tests; Risk; Sirolimus; TOR Serine-Threonine Kinases

Therapeutic drug monitoring (TDM) provides valuable guidance for dose adjustment of antibiotics, immunosuppressives, antiepileptics, and other drugs, but its use for traditional anticancer therapies has been limited. Perhaps the most important obstacle is the impractical requirement of multiple blood samples to adequately define systemic exposure of drugs that have a short elimination half-life and are given by intermittent intravenous injections. However, the newer targeted anticancer therapies have different pharmacokinetic (PK) and dosing characteristics compared with traditional cytotoxic drugs, making it possible to estimate the steady-state drug exposure with a single trough-level measurement. Recent evidence indicates that certain PK parameters, including trough levels, are correlated with clinical outcomes for many of these agents, including imatinib, sunitinib, rituximab, and cetuximab. Although the current evidence is insufficient to mandate TDM in routine practice, a concerted investigation should be encouraged to determine whether the steady-state trough measurements of targeted agents will have a practical place in the clinical care of patients with cancer.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Area Under Curve; Benzamides; Benzenesulfonates; Cetuximab; Dasatinib; Drug Monitoring; Everolimus; Evidence-Based Medicine; Half-Life; Humans; Imatinib Mesylate; Indoles; Injections, Intravenous; Molecular Targeted Therapy; Neoplasms; Niacinamide; Phenylurea Compounds; Piperazines; Pyridines; Pyrimidines; Pyrroles; Rituximab; Sirolimus; Sorafenib; Sunitinib; Thiazoles

PI3K/AKT/mTOR pathway is a crucial mediator of tumor progression. As the PI3K/Akt pathway is heavily deregulated in breast cancer, the application of mTOR inhibitors in breast cancer patients seems warranted. This is the first systematic review according to PRISMA guidelines to synthesize all available data of mTOR inhibitors in all subcategories of breast cancer. The search strategy retrieved 16 studies evaluating everolimus (1492 patients), seven studies examining temsirolimus (1245 patients), one study evaluating sirolimus (400 patients) and two studies evaluating MKC-1 (60 patients). The Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study has marked a turning point in the evaluation of everolimus in the treatment of estrogen receptor positive breast cancer. Given the positive results, everolimus has entered NCCN 2012 guidelines, and its approval of its combination with exemestane by FDA and EMA is imminent. In addition, the promising antitumor activity and long-term disease control further suggest that mTOR inhibition with everolimus may provide an avenue for achieving long-lasting benefit from trastuzumab-based therapy in HER2-positive patients. Regarding temsirolimus, it seems that the agent may play, in the future, a role in the treatment of metastatic breast cancer; importantly, however, there is an unmet need to find its optimal target subpopulation.

Topics: Breast Neoplasms; Everolimus; Humans; Receptor, ErbB-2; Receptors, Estrogen; Sirolimus; TOR Serine-Threonine Kinases

Topics: Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The characterization of the mantle cell lymphoma (MCL) entity had a major impact on patient management and has played a profound role in improving therapy. Although the prognosis is improving in MCL, there is no definitive proof that the therapies currently available will lead to cure. Few randomized studies have been conducted in MCL patients. In young patients, initial intensive therapy with high-dose cytarabine followed by high-dose chemotherapy and hematopoietic stem cell reinfusion has resulted in prolonged progression-free survival. In elderly subjects, who always represent a more heterogeneous group of patients, there is no consensus concerning which drugs can be used during induction chemotherapy. New drugs have essentially been evaluated in patients with recurrent disease or refractory to first-line regimens. Recently, two of them (bortezomib and temsirolimus) with different modes of action were registered in MCL. Targeted therapies are also being investigated extensively in MCL and are yielding interesting activities.

Topics: Adult; Age Factors; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cytarabine; Disease-Free Survival; Dose-Response Relationship, Drug; Drugs, Investigational; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Prognosis; Pyrazines; Recurrence; Salvage Therapy; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; Watchful Waiting

Approaches to treatment for many patients with advanced breast cancer are based on the expression of specific receptors. Treatments targeting the hormone receptor (typically the estrogen receptor) are used to reduce signaling through these receptors and thereby inhibit proliferation of breast cancer cells expressing these receptors. Although these treatments are effective for many patients, resistance to treatment is common. Recent clinical trials suggest that using multiple agents targeting the same pathway is not sufficient to overcome resistance. New treatment approaches are needed for these patients. Inhibition of the mTOR signaling pathway, a key point of confluence for multiple signaling cascades, offers a promising approach to restoring sensitivity to endocrine therapy in breast cancer. This article reviews the current data from studies of mTOR inhibitors everolimus and temsirolimus in combination with endocrine therapies to overcome treatment resistance in patients with advanced breast cancer.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Sirolimus; TOR Serine-Threonine Kinases

Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-α, in recent years several targeted therapies have become available for first- and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-α), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Combined Modality Therapy; Disease-Free Survival; Everolimus; Humans; Immunotherapy; Indoles; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

The introduction of molecular targeted therapies for patients with metastatic renal cell carcinoma has provided treatment options that are more efficacious and better tolerated than cytokine therapy, the previous standard of care. These advances have led to renewed efforts to define the health-related quality of life (HRQOL) impact of disease status stabilization or improvement versus that of treatment-associated adverse events. The distinct classes of targeted agents have unique AE profiles related to their specific targets; therefore, treatment considerations should include the patient's pretreatment HRQOL along with the known HRQOL effects of each drug. With more second- and third-line treatment options available for patients with metastatic renal cell carcinoma, HRQOL outcomes in earlier lines of therapy may guide treatment decisions for subsequent therapy, as poor HRQOL at therapy onset predicts poor survival. Both general and disease-specific instruments are used in clinical trials to reveal the impact of treatment on patient-reported outcomes. In this article, the common instruments used to assess HRQOL and the HRQOL outcomes observed in pivotal trials of targeted therapies are reviewed. Current data indicate that first-line therapy with sunitinib and first-line therapy in poor-prognosis patients with temsirolimus provide improved HRQOL compared with interferon-α. First- and second-line therapy with pazopanib and second-line therapy with everolimus and sorafenib maintained HRQOL levels similar to placebo, indicating that these agents do not worsen HRQOL. The HRQOL effects of bevacizumab plus IFN-α have not been reported. As new agents enter clinical investigation, HRQOL data can help determine their overall role in treatment.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Indoles; Interferon-alpha; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quality of Life; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

Targeted therapy for advanced renal cell carcinoma (RCC) has recently expanded the available treatment options for patients with these malignancies. The rapid introduction of novel treatment options into clinical practice within a relatively short time frame has created some new challenges pertaining to adverse event (AE) management in patients with advanced RCC. Accumulating safety data from the pivotal phase III clinical trials of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab plus interferon, VEGF receptor tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have served to characterize the toxicity profiles of these novel agents. Overall, it is evident that RCC-directed targeted therapy differs from immunotherapy and cytotoxic chemotherapy in terms of a number of unique nonhematologic AEs (some of which have not been traditionally encountered in oncology practice) and that there are distinctions within and across the various classes of agents with respect to the most prominent AEs and the risk for less common but serious complications. Although treatment-associated AEs are common, the majority of AEs reported during clinical trial experiences were grade 1 or 2 in severity and manageable with intervention in the form of supportive measures and/or dosage modification. Therefore, despite the relatively complex AE profiles of RCC-directed targeted therapy, patient education, consistent monitoring with a focus on early detection by health care providers (oncologists, general physicians, nurses), and the application of emerging AE management strategies may allow for prolonged treatment in most patients with advanced RCC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Everolimus; Humans; Immunotherapy; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Therapeutic options in advanced renal-cell cancer have expanded through better understanding of molecular pathology and development of novel targeted therapeutics. Vascular endothelial growth factor, the key ligand of angiogenesis, has a major role in the progression of vascularized kidney tumors and this is the target molecule of modern medications. The three types of the mechanism of action of current therapies are: monoclonal antibodies blocking directly vascular endothelial growth factor ligand (bevacizumab), tyrosine-kinase inhibitors blocking vascular endothelial growth factor receptors (sorafenib, sunitinib, pazopanib) and inhibitors of the intracellular mTOR-kinase (temsirolimus, everolimus). Based on randomized studies, sunitinib, pazopanib or interferon-α-bevacizumab combination should be the first-line therapy in patients with good/moderate prognosis, while temsirolimus is recommended in those with poor prognosis. Following an ineffective cytokine therapy sorafenib or pazopanib are the second-line treatment. In case of tyrosine-kinase inhibitor inefficacy, current evidence favors everolimus. Patient outcome can further be improved by the involvement of more modern and effective target products.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of molecular targeted drugs have revolutionized the treatment for patients with metastatic RCC (mRCC). Multi-targeted tyrosine kinase inhibitors (sorafenib and sunitinib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have recently shown superiority over interferon-α or placebo. However, while the molecular targeted drugs have demonstrated encouraging results, these drugs have also sometimes induced unexpected adverse events. Control of adverse events is important to obtain the maximum effectiveness and sustain quality of life for patients. Because renal pelvic cancer has many similarities in pathogenesis with urinary bladder cancer, the same chemotherapeutic regimen is often proposed for patients with metastatic renal pelvic cancer. Combined chemotherapy with gemcitabine and cisplatin is now widely considered to be first-line chemotherapy against these metastatic diseases; however, there are still unresolved problems with this treatment, including the limited survival benefit. To select new therapeutic modalities, a more profound understanding of the molecular biology of renal pelvic cancer is crucial. The purpose of this review is to summarize the current evidence supporting the role and activities of new chemotherapeutic agents and to reveal potential future directions in the management of mRCC and renal pelvic cancer.

Topics: Benzenesulfonates; Carcinoma, Renal Cell; Cisplatin; Deoxycytidine; Everolimus; Gemcitabine; Humans; Indoles; Kidney Neoplasms; Kidney Pelvis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

The median survival of patients with metastatic renal cell carcinoma (mRCC) increased from 10 to more than 40 months since the advent of targeted therapy. The transformation of mRCC from an initially lethal disease to a more favorable entity, albeit incurable, occurred with the transition from best supportive care, to cytokines, to finally sequential targeted therapies. Sunitinib and bevacizumab (level 1b) represent the first-line standard of care for patients with clear-cell mRCC vs temsirolimus (level 2) for those with high-risk features. Additionally, exploratory analyses of the temsirolimus data indicate important benefits for those with nonclear-cell mRCC histological subtypes. In second-line, everolimus proved its efficacy (level 1b). Nonetheless, sunitinib and sorafenib are also effective for nonclear-cell histological subtypes and after failure of other first-line treatment. The PFS benefits of first- and subsequent treatment-lines were confirmed in virtually all subgroup analyses. Potential survival benefits can be derived from cytoreductive nephrectomy (CNT), as was shown for cytokines in the general population, in sunitinib and bevacizumab-exposed patients. Phase III studies are ongoing to address the importance of CNT. This information is crucial to ensure timely delivery of a combination of medical and surgical therapies in this patient population.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Immunotherapy; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Neoplasm Metastasis; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

With an explosion of available treatments for metastatic renal cell carcinoma (mRCC) in recent years, it is important to recognize that approved targeted therapies fall broadly into only two mechanistic categories. The first category, vascular endothelial growth factor (VEGF)-directed therapies, includes sunitinib, pazopanib, sorafenib and bevacizumab. The second category includes inhibitors of the mammalian target of rapamycin (mTOR), namely everolimus and temsirolimus. A pivotal trial of everolimus supports use of the agent in patients with mRCC refractory to VEGF- tyrosine kinase inhibitors (TKI) therapy, while pivotal data for temsirolimus supports use in poor-prognosis patients as first-line therapy. Multiple reviews exist to delineate the laboratory and clinical development of mTOR inhibitors. This paper will outline the future applications of these therapies. It will explore ongoing trials evaluating combinations of mTOR inhibitors with other targeted therapies, along with sequencing strategies and biomarker discovery efforts. The application of mTOR inhibitors in unique populations is also described.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Sirolimus; TOR Serine-Threonine Kinases

The toxicities of newer targeted therapies are different from those seen with the traditional chemotherapy. Mammalian target of rapamycin (mTOR) inhibitors are evolving into an important class of drugs in oncology, and this class of drugs presents with a variety of different toxicities. Although similar to the toxicities seen in transplantation, these rapamycin analogs have unique side effects when compared to traditional chemotherapy agents. While most of the toxicities are mild, few can be severe and require routine monitoring. Mucositis and rash are the most common side effects. The metabolic toxicities, hyperglycemia, hyperlipidemia, and hypophosphatemia are different from the side effects traditionally seen with chemotherapy. This review will focus on the common toxicities seen with the mTOR inhibitors.

Topics: Antineoplastic Agents; Everolimus; Humans; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

It has been two years since molecular-targeted therapy became available for advanced renal cell carcinoma (RCC) in Japan. It shall be validated whether molecular-targeted therapy really improved the prognosis of patients with advanced RCC in the near future. Here we review the two phase III clinical studies that demonstrated the superiority of sunitinib and temsirolimus over IFNα and discuss optimal therapy including IFNα for advanced RCC in the future biomarker era.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Humans; Indoles; Interferon-alpha; Molecular Targeted Therapy; Pyrroles; Sirolimus; Sunitinib

Better understanding of the molecular biology of renal cell carcinoma (RCC) has led to the development of several targeted anti-cancer agents, several of which have since received approval for treatment of advanced disease. Two of these, the intravenous agent temsirolimus and the oral everolimus, exhibit antitumor effects through inhibition of the mammalian target of rapamycin (mTOR) pathway. This article reviews their mechanisms of action in the context of the current understanding of RCC pathophysiology, the clinical data leading to their approval, class-specific toxicities, potential molecular mechanisms behind treatment resistance and novel treatment approaches for RCC that incorporate mTOR blockade.

Topics: Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Kidney Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is a new targeted therapy used in advanced renal cell carcinoma and mantle cell lymphoma and is currently tested in several other human tumors. It induces several cutaneous and mucosal side effects, including painful, dose-limiting stomatitis. We report the unusual case of a 77-year-old man who developed severe mucosal, scrotal and perianal cutaneous aphthous-like ulcerations, 6 weeks after introduction of temsirolimus therapy for advanced-stage renal cell carcinoma. Other causes of aphthous-like ulcerations were ruled out. Topical corticosteroids remained ineffective. It led to the interruption of the treatment. Introduction of colchicine resulted in a dramatic improvement within 1 month. Reintroduction of temsirolimus with concomitant colchicine therapy was followed by a delayed recurrence of the lesions. We provide here a review of the potential cutaneous and mucosal side effects of mTOR inhibitors.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Genital Diseases, Male; Humans; Kidney Neoplasms; Male; Protein Kinase Inhibitors; Scrotum; Sirolimus; Stomatitis, Aphthous; TOR Serine-Threonine Kinases

Hepatocellular carcinoma (HCC) is a major health problem worldwide. Several molecular pathways involved in HCC growth and progression have recently been identified. Rapamycin analogs are able to inhibit one of the most active oncogenic molecular pathways in HCC cells: the mammalian target of rapamycin (mTOR) pathway.. In this review, the authors analyze the principal molecular features of the mTOR pathway and the use of rapamycin analogs in the treatment of hepatocarcinoma. The article also looks at the reoccurrence of HCC following liver transplantation as well as after the treatment of de novo neoplasms. Finally, the authors discuss the advantage of using a combined HCC pharmacological therapy to obtain a synergistic effect on tumor mass.. Among the available options for the treatment of advanced-stage HCC, mTOR pathway inhibitors show great promise. Once these agents have their safety and efficacy confirmed, in the treatment of liver disease, their use should be considered in patients affected by HCC. This should especially be the case for those who have had liver transplants or suffered with de novo tumors. Moreover, the authors believe that mTOR inhibitors could be used in a combined pharmacological approach to improve HCC molecular-targeted therapy by producing a multiple-level block of tumor intracellular signaling.

Topics: Animals; Carcinoma, Hepatocellular; Clinical Trials as Topic; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Liver Neoplasms; Liver Transplantation; Molecular Targeted Therapy; Neoplasm Staging; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To assess the clinical effectiveness and cost-effectiveness of bevacizumab, combined with interferon (IFN), sorafenib tosylate, sunitinib and temsirolimus in the treatment of people with advanced and/or metastatic renal cell carcinoma (RCC).. Electronic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched up to September/October 2007 (and again in February 2008).. Systematic reviews and randomised clinical trials comparing any of the interventions with any of the comparators in participants with advanced and/or metastatic RCC were included, also phase II studies and conference abstracts if there was sufficient detail to adequately assess quality. Results were synthesised narratively and a decision-analytic Markov-type model was developed to simulate disease progression and estimate the cost-effectiveness of the interventions under consideration.. A total of 888 titles and abstracts were retrieved in the clinical effectiveness review, including reports of eight clinical trials. Treatment with bevacizumab plus IFN or sunitinib had clinically relevant and statistically significant advantages over treatment with IFN alone, in terms of progression-free survival and tumour response, doubling median progression-free survival from approximately 5 months to 10 months. Temsirolimus had similar advantages over treatment with IFN in terms of progression-free and overall survival, increasing median overall survival from 7.3 to 10.9 months [hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58 to 0.92)], as did sorafenib in comparison with best supportive care in terms of overall survival, progression-free survival and tumour response, with a doubling of progression-free survival (HR 0.51; 95% CI 0.43 to 0.60). However, the last was associated with an increased frequency of hypertension and hand-foot skin reaction compared with placebo. No fully published economic evaluations of any of the interventions could be located. However, estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of 30,000 pounds per quality-adjusted life-year (QALY). Estimates of cost per QALY ranged from 71,462 pounds for sunitinib to 171,301 pounds for bevacizumab plus IFN. Although there are many similarities in the methodology and structural assumptions employed by PenTAG and the manufacturers of the interventions, in all cases the cost-effectiveness estimates from the PenTAG model were higher than those presented in the manufacturers' submissions. Cost-effectiveness estimates were particularly sensitive to variations in the estimates of treatment effectiveness, drug pricing (including dose intensity data), and health-state utility input parameters.. Treatment with bevacizumab plus IFN and sunitinib has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC. In people with three of six risk factors for poor prognosis, temsirolimus had clinically relevant advantages over treatment with IFN, and sorafenib tosylate was superior to best supportive care as second-line therapy. The frequency of adverse events associated with bevacizumab plus IFN, sunitinib and temsirolimus was comparable with that seen with IFN, although the adverse event profile is different. Treatment with sorafenib was associated with a significantly increased frequency of hypertension and hand-foot syndrome. Estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of 30,000 pounds per QALY.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cost-Benefit Analysis; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Temsirolimus, an ester of sirolimus (rapamycin), selectively inhibits the kinase mammalian target of rapamycin and consequently blocks the translation of cell cycle regulatory proteins and prevents overexpression of angiogenic growth factors. Patients with advanced renal cell carcinoma (RCC) and a poor prognosis who received a once-weekly intravenous (IV) infusion of temsirolimus 25 mg, experienced significant survival benefits when compared with patients receiving standard interferon-alpha (IFNalpha) therapy in a large phase III clinical study. In this study, median overall survival was 10.9 vs. 7.3 months and objective response rates were 8.6% in temsirolimus recipients vs. 4.8% IFNalpha recipient group.Temsirolimus monotherapy recipients experienced significantly fewer grade 3 or 4 adverse events and had fewer withdrawals for adverse events than patients receiving IFNalpha.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Intracellular Signaling Peptides and Proteins; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

A more profound understanding in the pathophysiological mechanism of renal cell cancer has led to a shift in the treatment approach. Traditionally, cytokines were the frontline drugs, but recently this has transitioned to drugs interacting vascular endothelial growth factor (VEGF) related pathway. Sorafenib, sunitinib, bevacizumab, temsirolimus and everolimus have demonstrated clinical improvements in randomized trials. The purpose of this review is to summarise the current management of advanced RCC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cell Transformation, Neoplastic; Everolimus; Humans; Indoles; Kidney Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Von Hippel-Lindau Tumor Suppressor Protein

Several molecular therapies have recently become available in first-line therapy of metastatic renal cell carcinoma (mRCC), thus marginalizing cytocine-based therapy. The primary aim of treatment in this situation is to delay progression with an increase in long-term life expectancy along with enhanced quality of life. At present, three new substances are available: Sunitinib, Temsirolimus, and - in combination with Interferon-alpha - Bevacizumab. To date, sufficient data is at hand for all drugs, which has resulted in a consolidation of therapeutic strategy. Selecting the best therapy is highly relevant in everyday practice, depending, among other things, on clinical evidence, guidelines, and the respective approval status. The prognostic score according to Motzer (MSKCC) plays a major role. It covers three prognostically relevant risk groups which are important for the preferential application of the new substances. Current recommendations suggest the application of Sunitinib and Bevacizumab plus Interferon-alpha for good and medium prognoses, with Sunitinib being regarded to be one therapy of first choice. It is the most frequently applied substance for this indication in Germany. The efficacy of Temsirolimus has been documented for patients with poor prognosis and it has been approved for this indication only. Hence, the mTor inhibitor should be the standard for this group of patients.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease Progression; Drug Delivery Systems; Drugs, Investigational; Evidence-Based Medicine; Germany; Humans; Indoles; Interferon-alpha; Kidney Neoplasms; Prognosis; Pyrroles; Sirolimus; Sunitinib; Survival Rate

Since the late 1990's, novel insights into molecular biology and carcinogenesis enabled the rational design of mechanism-based anticancer therapeutics. The large number of natural product (NP)-derived drugs currently under clinical evaluation and the recent approval of temsirolimus (Torisel) as a first mTOR protein kinase inhibitor indicate that NPs have to be considered not only as a seminal source of cytotoxic, but also as a source of molecularly targeted agents. Whereas molecular modeling is well established as an important and successful method to discover and rationalize bioactivities in medicinal chemistry research, its application has also proven to be also a powerful tool in the field of NPs. This review highlights the impact of computer-assisted approaches on NPs as molecularly targeted anticancer drugs. Examples of applications are provided focusing on innovative targets such as protein kinases, tumour vasculature, epigenetic modulators, heat shock protein (Hsp) 90, and direct apoptosis enhancers.

Topics: Antineoplastic Agents; Apoptosis; Biological Products; Drug Design; Epigenesis, Genetic; HSP90 Heat-Shock Proteins; Models, Molecular; Plant Preparations; Sirolimus; Structure-Activity Relationship

The inhibitors of the mammalian target of rapamycin (mTOR) improve outcomes in patients with advanced renal cell carcinoma. These agents are associated with unusual class-adverse events that represent a challenge to the clinician, making it critical to recognize and treat them appropriately. This study aims to highlight the clinical management of these toxicities by presenting evidence from the literature and suggesting treatment recommendations. A critical review of the literature is performed and a summary of the most relevant emergent toxicities and their management is presented. Treatment recommendations of metabolic disturbances induced by mTOR inhibitors, such as hypophosphatemia, hyperglycemia, and hyperlipidemia along with the management of drug-induced pneumonitis and possible pharmacological interactions are presented. Most of these toxicities, if recognized and treated accordingly, should resolve with minimal impact on patients' quality of life and in the efficacy of this anticancer therapy. Oncologists should be familiar with the recognition and appropriate medical management of these clinical scenarios.

Topics: Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Everolimus; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

Locally advanced renal tumors show a high progression rate after surgery. Surgical treatment of renal tumors has some unique characteristics related to involvement of the adrenal gland, vena cava, or regional lymph nodes.. To review the current treatment of locally advanced renal tumors.. A review is made of both the different drugs used and the different therapeutic possibilities in these tumors.. Systemic treatment with angiogenesis inhibitors may improve the natural history of these patients. Systemic treatment may be administered before surgery or as an adjuvant to surgical treatment. Early studies showed a decrease in tumor mass when treatment is administered before surgery, but no prospective randomized studies providing adequate evidence for recommending neoadjuvant treatment are available.. Availability of systemic treatment with angiogenesis inhibitors may open an important field in the treatment of these tumors in both the neoadjuvant setting and as adjuvants to surgery, but no sufficiently solid scientific evidence as to recommend their use is currently available. Randomized studies with sunitinib and sorafenib will probably suggest the adequate approach to be used when their final results are reported.

Topics: Adrenalectomy; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Lymph Node Excision; Neoadjuvant Therapy; Neoplasm Proteins; Nephrectomy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases

mTOR signaling pathway (mammalian target of rapamycin) is a major pathway in cell physiology and malignant behavior implicated in cell growth, cell proliferation, cell metabolism, protein synthesis and angiogenesis. Temsirolimus has shown in a randomized phase III trial for patients with poor risk feature of metastatic renal cell carcinoma, a significant gain in overall survival compared to this obtained with alpha interferon (7.3 à 10.9 months; HR: 0.73; P < 0.0069). Everolimus has shown in a randomized phase III trial for patients with metastatic renal cell carcinoma having failed under VEGFR tyrosine kinase inhibitor a significant gain in progression-free survival compared to this obtained with placebo VEGFR (1,8 à 4,6 months; HR: 0.33; P < 0.001). Temsirolimus and everolimus are now part of the reference treatments in renal cell carcinoma. This paper is a review of these two drugs in this setting.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Renal cell carcinoma (RCC) is the most prevalent kidney cancer and the 5-year overall survival figure in metastatic disease (mRCC) is about 10%. New targeted drugs (sunitinib, sorafenib, bevacizumab, temsirolimus) have shown activity in the treatment of mRCC, but they are all associated with a significant burden of cost. To support decision makers in their allocation of resources, costeffectiveness models are constructed to compare the costs and outcomes of anticancer therapy. This survey focuses on studies since 2003 exploring health economics in the treatment of metastatic and/or advanced RCC employing these new drugs. This paper summarizes the results, focuses on the level of evidence of these studies, compares the calculated cost-effectiveness ratios and makes suggestions for future studies. This review reveals costs per life years gained (LYG) or quality-adjusted life years (QALY) in the range of euro 22,648 to euro203,692, depending on whether the setting is first-line or second-line and drug used. When compared to the other agents, sunitinib has the best cost-effectiveness figure. Second-line therapy does not offer valid incremental cost-effectiveness ratios.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cost-Benefit Analysis; Humans; Indoles; Kidney Neoplasms; Markov Chains; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quality-Adjusted Life Years; Sirolimus; Sorafenib; Sunitinib

The median survival of patients with metastatic renal cell carcinoma (mRCC) has increased from 10 months to more than 40 months since the advent of targeted therapy. Sunitinib and bevacizumab represent the first-line standards of care for patients with clear cell mRCC. Temsirolimus is the standard of care for those with poor-risk features. Additionally, exploratory analyses of the temsirolimus data indicate important benefits for those with non-clear-cell mRCC. Everolimus has proved its efficacy in second-line therapy. Sunitinib and sorafenib are also effective for non-clear-cell histological subtypes and after failure of first-line treatment. Potential survival benefits can also be derived from cytoreductive nephrectomy (CNT) in patients previously exposed to sunitinib or bevacizumab. Phase III studies are ongoing to address the importance of CNT in the targeted therapy era. Such information is crucial to ensure timely delivery of a combination of medical and surgical therapies to this patient population.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Combined Modality Therapy; Humans; Interferons; Interleukin-2; Kidney Neoplasms; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyridines; Sirolimus; Sorafenib

Mammalian target of rapamycin (mTOR) protein complex functions as an integration center for various intracellular signaling pathways involving proliferation, cell survival, and angiogenesis. These pathways are frequently abnormally regulated in cancer. Notably, Akt is an upstream molecule which is over-expressed and/or activated in several cancers. Therefore, mTOR inhibitors can be options for the treatment of cancers. At present, mTOR inhibitors are applied to treat patients with metastatic renal cell carcinoma (RCC). Temsirolimus is indicated as the first line therapy for RCC patients with poor prognosis, whereas everolimus as the second line for those refractory to sorafenib or sunitinib. Interstitial pneumonia is the most serious adverse event for both agents. Clinical trials are under way to explore indications for various cancers.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Proliferation; Cell Survival; Clinical Trials as Topic; Everolimus; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Lung Diseases, Interstitial; Protein Serine-Threonine Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Since the middle of 1990s, the development of combinatorial chemistry along with the high throughput screening have led to some lack of interest for natural products from the pharmaceutical industry. Moreover, purification and optimization of natural compounds are very often difficult and animal experimentations need enough supply of natural sources or alternatively need sophisticated total synthesis. In oncology, this increased disinterest was also closely connected with the rapid expansion of monoclonal antibodies and synthetic protein kinase inhibitors. However since 2005, with the approval of five new drugs by the FDA (trabectedin, ixabepilone, temsirolimus, everolimus and Vinflunine), it appears that natural products are still present as direct or indirect sources of drugs. On the other hand, a third generation of natural product has arisen, which relies upon bioengineering using genetically altered producer organisms. This is particularly true of the polyketides where bioengineering harnesses their natural flexibility to expand their structural diversity. Several programs are going on to produce antibiotics, anticancer drugs or immunosuppressant. This combinatorial approach makes drug discovery by bioengineering complementary with conventional medicinal chemistry. With the approval of Mylotarg by the FDA, increased interest has also been devoted to immunoconjugates, which represent a way by which highly cytotoxic natural products such as dolastatin, calicheamycin, duocarmycin and maytansin may be targeted to cancer cells while limiting their side-effects.

Topics: Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bioengineering; Biological Products; Clinical Trials as Topic; Combinatorial Chemistry Techniques; Dioxoles; Drug Approval; Drug Discovery; Drug Screening Assays, Antitumor; Drugs, Investigational; Epothilones; Everolimus; Gemtuzumab; Humans; Immunoconjugates; Maytansine; Sirolimus; Tetrahydroisoquinolines; Trabectedin; United States; United States Food and Drug Administration; Vinblastine

Temsirolimus selectively inhibits the mammalian target of rapamycin (mTOR) kinase, with subsequent inhibition of the translation of cell cycle regulatory proteins. Therapy with intravenous temsirolimus 175 mg once weekly for 3 weeks followed by 75 mg once weekly (higher temsirolimus dosage), but not 25 mg once weekly (lower temsirolimus dosage), was significantly more effective than single-agent chemotherapy of the investigator's choice in terms of the primary endpoint of progression-free survival (PFS), as assessed by independent review, in the treatment of adult patients with relapsed and/or refractory mantle cell lymphoma in a phase III study. Both dosage regimens of temsirolimus achieved significantly better outcomes with regard to PFS, as assessed by the investigator (secondary endpoint), than the investigator's choice therapy. Patients receiving the higher temsirolimus dosage achieved a significantly better outcome with regard to the objective response rate (ORR) than those receiving the investigator's choice therapy; however, no significant difference in terms of ORR was observed between patients receiving the lower temsirolimus dosage and those receiving the investigator's choice therapy. The differences between the two temsirolimus treatment groups and the investigator's choice treatment group with regard to the endpoint of overall survival did not reach statistical significance. The tolerability profile of temsirolimus in this patient population was mostly consistent with the known toxicities of the agent. The incidence of thrombocytopenia was significantly higher and that of leukopenia significantly lower in patients receiving the higher temsirolimus dosage compared with those receiving the investigator's choice therapy. Adverse events were often managed with dose modifications.

Topics: Antibiotics, Antineoplastic; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Recurrence; Sirolimus

The potent inhibitor of the mammalian target of rapamycin, temsirolimus, comprises for cell cycle, angiogenesis and proliferation and has proven beneficial in the treatment of advanced renal cell carcinoma (RCC). Temsirolimus is officially approved for first line therapy in high risk previously untreated mRCC patients. This review summarizes the current clinical role of temsirolimus in the treatment of advanced renal cell carcinoma with regard to pharmacological features, toxicity and tolerability. It particularily discusses quality of life issues as important outcome parameters in palliative treatment of patients with mRCC and gives an outlook on current clinical developments regarding possible future combining/ sequencing strategies of temsirolimus.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Kidney Neoplasms; Quality of Life; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Discovery of new treatments for lymphoma that prolong survival and are less toxic than currently available agents represents an urgent unmet need. We now have a better understanding of the molecular pathogenesis of lymphoma, such as aberrant signal transduction pathways, which have led to the discovery and development of targeted therapeutics. The ubiquitin-proteasome and the Akt/mammalian target of rapamycin (mTOR) pathways are examples of pathological mechanisms that are being targeted in drug development efforts. Bortezomib (a small molecule protease inhibitor) and the mTOR inhibitors temsirolimus, everolimus, and ridaforolimus are some of the targeted therapies currently being studied in the treatment of aggressive, relapsed/refractory lymphoma. This review will discuss the rationale for and summarize the reported findings of initial and ongoing investigations of mTOR inhibitors and other small molecule targeted therapies in the treatment of lymphoma.

Topics: Boronic Acids; Bortezomib; Everolimus; Humans; Lymphoma; Molecular Targeted Therapy; Pyrazines; Signal Transduction; Sirolimus; Survival Analysis

The biological function of the mammalian target of rapamycin (mTOR) and mechanisms of action of mTOR inhibitors currently available for clinical use are described.. mTOR is a target for anticancer agents due to its role in cancer development, progression, and resistance to other antineoplastic agents. Currently, two mTOR inhibitors, temsirolimus and everolimus, are approved for the treatment of patients with advanced renal cell carcinoma (RCC). Clinical trials comparing single-agent temsirolimus with interferon alfa-2a demonstrated an improvement in overall survival and progression-free survival (PFS) in patients with metastatic RCC. Clinical studies comparing everolimus with placebo indicated improved PFS in advanced RCC patients whose disease had progressed on or after vascular endothelial growth factor (VEGF) inhibitor therapy. Due to its role in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, mTOR is a rational target for inhibition in combination with other agents, including traditional chemotherapy and agents that are affected by or target the PI3K pathway. Data from these studies review the use of mTOR inhibitors in non-Hodgkin's lymphoma and endometrial, breast, and neuroendocrine tumors. Common toxicities of mTOR inhibitors include mucositis, stomatitis, rash, asthenia, fatigue, and myelosuppression. Additional toxicities requiring monitoring include hyperglycemia, hyperlipidemia, and pneumonitis.. The mTOR signaling pathway is upregulated in a variety of solid and hematologic tumors. Two inhibitors of this pathway, temsirolimus and everolimus, have been approved for use in metastatic RCC. Although relatively safe, these drugs are associated with some unique adverse effects, such as hyperlipidemia, hyperglycemia, and pneumonitis, that require monitoring and may require clinical intervention.

Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Drug Design; Drug Monitoring; Drug Resistance, Neoplasm; Everolimus; Humans; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Over the last few years, targeted agents have assumed a predominant role in treatment of metastatic renal cell carcinoma (mRCC). Our aim is to discuss recent developments on this rapidly evolving topic.. Sunitinib represents front-line standard treatment for the good- and intermediate prognosis groups of patients with clear cell renal carcinoma. Bevacizumab/interferon and pazopanib have also been FDA-approved as first-line agents, while sorafenib has moved toward second-line and later therapy. Temsirolimus, an mTOR inhibitor, is recommended as front line therapy for patients in the poor-risk group and is the best front-line choice for patients with non-clear cell histology. Another mTOR inhibitor, everolimus, has shown clinical benefit post-tyrosine kinasis inhibitors failure in a phase III study and is considered the standard of care in this setting. Novel prognostic and efficacy markers might help to define most appropriate therapeutic strategy. Best sequence of use of these effective agents in mRCC patients remains up to the discretion of treating physician.. In light of the considerable advances in understanding the biology of mRCC, several new drugs have been recently developed, with an increasing number of treatment options. Several markers are under evaluation for diagnostic, prognostic and efficacy purposes. A treatment algorithm, based on the best scientific evidence produce so far, is presented and it will evolve as data from ongoing trials will be available.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Immunotherapy; Indazoles; Interferons; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Pyridines; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides; TOR Serine-Threonine Kinases

Treatment of patients with advanced renal cell carcinoma (RCC) has changed dramatically with the advent of targeted therapeutics. Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has proven beneficial in the treatment of advanced RCC with poor prognosis. The rationale for mTOR inhibitors in treatment of RCC, the pharmacokinetics and toxicities of temsirolimus, landmark clinical trials of temsirolimus in advanced RCC, and the indications for its use in the treatment of RCC are reviewed here. The status of temsirolimus in the rapidly evolving therapeutic landscape of advanced RCC is also discussed.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Interactions; Humans; Intracellular Signaling Peptides and Proteins; Liver Failure; Liver Neoplasms; Protein Serine-Threonine Kinases; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases

Treatment for metastatic renal cell cancer (mRCC) has advanced dramatically with understanding of the pathogenesis of the disease. New treatment options may provide improved progression-free survival (PFS). We aimed to determine the relative effectiveness of new therapies in this field.. We conducted comprehensive searches of 11 electronic databases from inception to April 2008. We included randomized trials (RCTs) that evaluated bevacizumab, sorafenib, and sunitinib. Two reviewers independently extracted data, in duplicate. Our primary outcome was investigator-assessed PFS. We performed random-effects meta-analysis with a mixed treatment comparison analysis.. We included 3 bevacizumab (2 of bevacizumab plus interferon-a [IFN-a]), 2 sorafenib, 1 sunitinib, and 1 temsirolimus trials (total n = 3,957). All interventions offer advantages for PFS. Using indirect comparisons with interferon-alpha as the common comparator, we found that sunitinib was superior to both sorafenib (HR 0.58, 95% CI, 0.38-0.86, P = < 0.001) and bevacizumab + IFN-a (HR 0.75, 95% CI, 0.60-0.93, P = 0.001). Sorafenib was not statistically different from bevacizumab +IFN-a in this same indirect comparison analysis (HR 0.77, 95% CI, 0.52-1.13, P = 0.23). Using placebo as the similar comparator, we were unable to display a significant difference between sorafenib and bevacizumab alone (HR 0.81, 95% CI, 0.58-1.12, P = 0.23). Temsirolimus provided significant PFS in patients with poor prognosis (HR 0.69, 95% CI, 0.57-0.85).. New interventions for mRCC offer a favourable PFS for mRCC compared to interferon-alpha and placebo.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indoles; Interferon-alpha; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib

PI3K/AKT/mTOR is a cell signalling pathway that plays a major role in regulation of apoptosis, cell growth and cell cycle. This pathway is often disregulated in human cancers, and constitutes an interesting target for antitumor therapy. Rapamycin is an inhibitor of mTOR that has first been developed for its immunosuppressive characteristics, as a preventive treatment of graft rejection. More recently, three rapamycin analogs have been developed, resulting in interesting results in preclinical studies on cancer cell lines : temsirolimus, everolimus, and deforolimus. These molecules are being tested in clinical studies, and both temsirolimus and everolimus have demonstrated efficacy in metastatic renal cancers. In contrast, perfosin, an AKT inhibitor, did not prove to be active in clinical studies. Many ongoing studies explore next indications of these drugs, given alone or in combination with chemotherapy or with other targeted therapy. Identification of predictive factors for sensibility to treatment represents another way of research.

Topics: Antineoplastic Agents; Cell Proliferation; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Humans; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

First-line therapies available for metastatic renal cell carcinoma (RCC) have increased rapidly with the recent introduction of three novel agents: sunitinib, temsirolimus and bevacizumab (in combination with interferon [IFN]). This expansion means that the selection of the optimal therapy for individual patients has become more difficult and increasingly important. A treatment algorithm based on tumour histology and patient risk status is currently used to guide clinical practice, but does not always allow specific treatment for individual patients to be identified. This is particularly true for the largest group of patients, who have favourable or intermediate risk clear cell RCC. Considerations guiding treatment selection for these patients include: potential for cure; and optimal progression-free survival (PFS) with good tolerability and quality of life. In patients who have a realistic opportunity for cure, bevacizumab combined with IFN might be the treatment of choice. However, sunitinib and bevacizumab combined with IFN produce similar PFS. Thus, if optimal PFS is the treatment goal, other factors must be considered. These include patient-related factors such as the needs, circumstances and comorbidities of individual patients and the associated side effects of bevacizumab combined with IFN and sunitinib. More data are currently available to support treatment decisions based on the latter and these are considered in detail, highlighting factors that may lead to selection of bevacizumab combined with IFN or sunitinib in individual patients.

Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Approval; Drug Design; Europe; Gastrointestinal Diseases; Hematologic Diseases; Humans; Indoles; Interferons; Kidney Neoplasms; Palliative Care; Patient Selection; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib; United States

The treatment options for metastatic renal cell carcinoma have expanded rapidly over the past 3 years, with four new agents available and others in late-stage development. This has resulted in a change of the standard of first-line care, with sunitinib or bevacizumab plus interferon the treatments of choice for patients with good or intermediate-risk renal cell carcinoma and temsirolimus treatment of choice for poor-risk disease. Sunitinib and bevacizumab plus interferon have similar efficacy, meaning that treatment choice is influenced by other factors: disease-related factors such as clear cell versus non-clear cell histology; patient factors such as co-morbidities, Memorial Sloan-Kettering Cancer Center risk and patient preference; and drug-related factors such as tolerability profile. The aim of this review is to describe the tolerability of the first-line treatment options for clear cell renal cell carcinoma, giving consideration to how tolerability profiles relate to drug mechanism of action. Thus, the incidence and aetiology of side effects related to vascular endothelial growth factor and vascular endothelial growth factor receptor inhibition using sunitinib and bevacizumab, as well as those of the non-specific side effects observed with sunitinib, are described. In addition, the potential patient impact and management of these side effects, as well as those of interferon and temsirolimus, are considered. Finally, the implications of the tolerability profiles of these agents for combination therapy and use in broader populations than those enrolled in trials are assessed.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blood Coagulation Disorders; Carcinoma, Renal Cell; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Disease-Free Survival; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hypothyroidism; Indoles; Interferons; Kidney Neoplasms; Multicenter Studies as Topic; Neoplasm Proteins; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sunitinib; Wound Healing

Renal cell carcinoma (RCC) encompasses a heterogeneous group of histological subtypes, of which clear cell RCC (CCRCC) is the most common, comprising more than 70% of all cases. Papillary RCC (PRCC) is the next most common, comprising 10-15% of cases. PRCC is refractory to chemotherapy, immunotherapy and hormonal therapy. Recent improvements in our understanding of the molecular biology of CCRCC have identified multiple pathways associated with the development of this cancer. This has led to drug development targeting these pathways, including the small molecule tyrosine kinase inhibitors sunitinib and sorafenib, the monoclonal antibody bevacizumab and the mTOR inhibitor temsirolimus. These drugs have shown significant clinical benefits in randomized trials of advanced CCRCC and have become the standard of care for most patients. However, since these trials were, on the whole, restricted to patients with clear cell histology, their efficacy in patients with non-clear cell RCC, and particularly PRCC, is unclear. This review will focus on the activity of these targeted agents in the treatment of metastatic PRCC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Papillary; Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Indoles; Kidney Neoplasms; Neoadjuvant Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Pyrroles; Quinazolines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases

Advanced renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy. Immunotherapy is relatively effective against RCC. However, the response rate is approximately 15-20%. Therefore, new therapeutic approaches are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC are identified, and molecular targeted therapy is developed. Bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus, everolimus are promising molecular targeted therapeutic agents for metastatic RCC, and will be used widely in clinics in the near future. In addition, combination therapy with molecular targeted therapy and other therapies including immunotherapy may also be developed soon.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Targeted therapies are widely used in cancer because of their effectiveness, even in tumours that are resistant to conventional chemotherapy such as kidney or hepatocellular carcinomas. There are different families classified according to their mode of action. The antiangiogenics block tumor angiogenesis by acting on VEGF or its receptor. The main molecules are bevacizumab, sunitinib, and sorafinib. HER inhibitors work by blocking these receptors, which control different signaling intracellular pathways, and include an inhibitor of HER2, trastuzumab, and various inhibitors of HER1, or EGFR, including cetuximab, erlotinib, and gefitinib. Inhibitors of KIT, a membrane receptor, are mainly represented by imatinib, an inhibitor of tyrosine kinase. Finally, mTOR inhibitors act on the signaling pathway PI3K/AKT/mTOR, and key molecules are temsirolimus, everolimus, and deforolimus.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; ErbB Receptors; Erlotinib Hydrochloride; Everolimus; Gefitinib; Humans; Indoles; Kidney Neoplasms; Liver Neoplasms; Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quinazolines; Receptor, ErbB-2; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

The development of targeted molecules in renal carcinogenesis changed the therapeutic approaches of treatment for metastatic clear cell renal cell carcinoma. Four available drugs are currently available, i.e. bevacizumab, sunitinib, sorafenib and temsirolimus, but other molecules and combined therapy are under investigation. In this review we assess published reports of these targeted therapies and discuss the novel promising molecules targeting vascular endothelial growth factor and its receptors, the mammalian target of rapamycin and epithelial growth factor cascade.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factors

The treatment of metastatic renal cell carcinoma (mRCC) has been changed by the introduction of targeted agents. Consideration of individual patient factors, such as previous treatment and prognostic risk, e.g. according to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria), can assist in ensuring that patients receive appropriate targeted therapies. Available clinical evidence shows sunitinib to be the reference standard of care for the first-line treatment of mRCC in patients at favourable or intermediate prognostic risk according to MSKCC criteria. Combined treatment with bevacizumab plus interferon-alpha can also be considered for the first-line treatment of mRCC in this setting. For the first-line treatment of poor-risk patients, temsirolimus has shown benefit in a phase III study, while sunitinib can also be considered. For second-line treatment in cytokine-refractory patients, sorafenib is recommended based on phase III trial results; sunitinib has also shown activity after failure of cytokine therapy or targeted agents. As well as antitumour activity, the tolerability of targeted agents should be evaluated in the context of individual patients, considering factors such as comorbidities and age. As our understanding of the activity of targeted agents for mRCC increases, we should ensure that these agents are used appropriately to provide patients with optimal treatment benefits.

Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Humans; Indoles; Interferon-gamma; Kaplan-Meier Estimate; Kidney Neoplasms; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib; Treatment Outcome

The mammalian target of rapamycin (mTOR) is clearly an important therapeutic target for advanced renal cell carcinoma (RCC), although its mechanisms of activation are not completely understood. In first-line treatment of patients who have both advanced RCC and multiple risk factors for short survival, temsirolimus improves overall survival (OS) compared with interferon. In patients whose tumors have progressed after sunitinib and/or sorafenib therapy, everolimus improves progression-free survival compared with placebo. Beyond the initial phase 3 studies demonstrating efficacy, many important questions remain in the clinical application of mTOR inhibition and in developing other inhibitors of PI3K/Akt/mTOR signaling. Important objectives of current and future clinical investigations include a more detailed description of the molecular pathology of RCC and identification of potential biomarkers that are predictive of tumor sensitivity to PI3K/Akt/mTOR targeted therapies. This information may identify other groups of RCC patients that are likely to benefit from inhibition of this signaling pathway. Additional questions concern mechanisms by which tumors become resistant to mTOR inhibitor therapy and how such resistance can be defeated. Possible mechanisms include the loss of feedback inhibition of insulin receptor substate/PI3K signaling resulting from the inhibition of mTOR complex 1 by rapamycin analogs and the activating phosphorylation of Akt by mTOR complex 2. Laboratory studies indicate that these resistance mechanisms could be countered by using other targeted agents in combination with mTOR inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Delivery Systems; Drug Resistance, Neoplasm; Everolimus; Humans; Interferons; Kidney Neoplasms; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The availability of active monoclonal antibodies, either as single agents or in combination with cytotoxic agents, has improved treatment results in non-Hodgkin's lymphoma (NHL). Despite this and the increasing number of available active monoclonal antibodies, alone or conjugated with radioisotopes, not all types of lymphoma are sensitive to these biological agents and often they become resistant because of different molecular mechanisms. New molecular targets in neoplastic cells are emerging and provide the rationale for novel discovery initiatives. In fact, a greater knowledge of the biology of lymphoma and the identification of compounds selectively active against a potential therapeutic pathway have already improved the time to progression and survival time of patients with some subtypes of NHL. The growing list of new drugs provides the exciting prospect of developing disease-specific and even patient-specific therapies. The aim of this review is to identify and discuss non-monoclonal antibody new therapeutic agents in terms of mechanism of action and clinical results. The preclinical and clinical features of proteasome inhibitors, histone deacetylase inhibitors, thalidomide and lenalidomide, mammalian target of rapamycin inhibitors, antisense oligonucleotides, heat shock protein inhibitors, protein kinase C inhibitors, antiangiogenic agents, and new cytotoxics are reviewed.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Boronic Acids; Bortezomib; Clinical Trials as Topic; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Lymphoma, Non-Hodgkin; Oligonucleotides, Antisense; Proteasome Inhibitors; Protein Kinase C; Pyrazines; Sirolimus

The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin-pathway (PI3K/AKT/mTOR-pathway) plays a role in the regulation of cell proliferation, cell survival, angiogenesis and resistance to anti-tumor treatments. In many tumor types the PI3K/AKT/mTOR-pathway is found activated through several different underlying mechanisms. Since this pathway is believed to largely drive the malignant behavior of several of these tumors, mTOR-inhibition is considered an attractive means to apply as anti-tumor treatment. Currently, four mTOR-inhibitors are explored for clinical use: rapamycin, temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573). As monotherapy, mTOR-inhibitors yield interesting anti-tumor activity against various tumor types at the expense of relatively mild toxicities. This recently resulted in the registration of two mTOR-inhibitors for patients with metastatic renal cell carcinoma (RCC) while randomized studies in other tumors are currently in progress. Furthermore, mTOR-inhibitors are well-suited drugs to combine with other anti-tumor drugs as in preclinical models mTOR-inhibition overcomes chemoresistance. Consequently, mTOR-inhibitor-containing multidrug regimens are subject to clinical studies. As holds true for all anti-tumor therapies, identification of patients who are likely to respond to mTOR-inhibitor-containing therapies is of utmost importance to avoid over- or undertreatment. Preliminary results suggest that several factors reflecting activation of mTOR in tumors may be used for this purpose. This review addresses the mechanism of action and current clinical experience with mTOR-inhibitors as well as their role in overcoming resistance to conventional therapies. Additionally, potential predictors of outcome to mTOR-inhibition are discussed.

Topics: Cell Division; Cell Survival; Clinical Trials as Topic; Drug Resistance, Neoplasm; Everolimus; Gene Amplification; Humans; Neoplasms; Neovascularization, Pathologic; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a targeted mechanism in the treatment of renal cell carcinoma (RCC). Temsirolimus, an mTOR inhibitor that is approved for treatment of advanced RCC, has demonstrated both overall survival benefits and progression-free survival benefits versus interferon-alpha as first-line treatment for patients with poor prognostic features. Exploratory subset analyses indicated that temsirolimus benefits patients with RCC regardless of tumor histology or nephrectomy status. Everolimus, the second mTOR inhibitor to demonstrate activity in RCC, improved progression-free survival versus placebo in patients whose disease progressed after treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (sunitinib, sorafenib, or both); benefit was observed for all risk groups. Deforolimus also exhibited antitumor activity against RCC in early clinical studies. There is now compelling clinical evidence for the effectiveness of targeting mTOR in the treatment of RCC.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Delivery Systems; Everolimus; Humans; Kidney Neoplasms; Models, Biological; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

To review the common and serious toxicities associated with the use of tyrosine kinase inhibitors such as sorafenib and sunitinib and mTOR inhibitor temsirolimus, and to outline the most recent toxicity management guidelines.. Common grade 3 or 4 side effects with sorafenib include lymphopenia (13%), hypophosphatemia (13%), elevated lipase (12%), hand-foot syndrome (6%), and mucositis/stomatitis (6%). Common grade 3 or 4 side effects with suntinib elevated lipase (16%), neutropenia (12%), lymphopenia (12%), hypertension (8%), and fatigue/asthenia (7%). As for temsirolimus, common grade 3 or 4 side effects consist of anemia (20%), hyperglycemia (11%), fatigue/asthenia (11%), dyspnea (9%), and hypophosphatemia (5%). Intracranial hemorrhage (ICH) is rare but occurred in sorafenib-exposed and sunitinb-exposed patients. Cardiovascular morbidity may also be observed in sorafenib-exposed and sunitinib-exposed patients.. Through preventive and therapeutic measures, these side effects can be effectively managed, without reducing the dose and, therefore, affecting the efficacy of the treatment.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Practice Guidelines as Topic; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

The importance of angiogenesis in tumour growth and development is well known. Overexpression of vascular endothelial growth factor (VEGF), the key mediator of angiogenesis, is associated with poor prognosis in cancer. As a result, several therapeutic agents that inhibit the actions of VEGF or its receptors are currently in development for use in advanced solid tumours, such breast, colorectal, lung and renal cancer. Clinical data from trials of anti-VEGF agents in this group of tumours are discussed, with a particular focus on the efficacy and safety of bevacizumab, the anti-VEGF agent at the most advanced stage of development in those tumour types. Future potential uses of bevacizumab in cancer therapy will be discussed.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Clinical Trials as Topic; Combined Modality Therapy; Drug Delivery Systems; Forecasting; Humans; Indoles; Neoadjuvant Therapy; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Renal cell carcinoma is the most common form of kidney cancer worldwide, and is associated with poor survival. Approximately a third of patients diagnosed with renal cell carcinoma present with metastatic disease and a further third experience recurrence following treatment for localized disease. Until recently, the cytokines interferon-alpha and interleukin-2 were the only effective treatments available for metastatic renal cell carcinoma and were associated with a modest increase in survival in a limited subset of patients. The prognosis for metastatic renal cell carcinoma has dramatically improved with the development of novel targeted agents including the oral tyrosine kinase inhibitors, sunitinib and sorafenib. However, renal cell carcinoma and the therapies used to treat patients with renal cell carcinoma are associated with a range of symptoms and treatment-related adverse events which contribute to the burden of disease. Common adverse events associated with targeted agents include fatigue, gastrointestinal and skin-associated toxicities. These adverse events, while mostly mild and manageable, affect the patients' health-related quality of life. As this review of the available quality of life data shows, assessment of the impact of the disease and its treatment on health-related quality of life may influence the choice of treatment and highlights the importance of incorporating patient-reported outcomes in clinical trials.

Topics: Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Renal Cell; Everolimus; Health Status; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Patient Satisfaction; Phenylurea Compounds; Pyridines; Pyrroles; Quality of Life; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

The diagnosis, staging, and management of renal cell carcinoma (RCC) are reviewed. The mechanism, pharmacokinetics, toxicity, clinical activity, and application of molecularly targeted agents in RCC are emphasized.. RCC is the eighth most commonly diagnosed malignancy in the United States. The most common signs and symptoms are gross hematuria, flank pain, and the presence of a flank mass. Localized disease is found in about 55% of patients, 19% of patients have locally advanced disease, and 20% of patients have metastatic disease. Surgical resection is the mainstay of therapy for stage I-III RCC. The pharmacotherapy of RCC is undergoing significant change. Standard therapy used to include the cytokines interferon alfa and aldesleukin. High-dose aldesleukin is used to treat select patients. Its major value is the durability of responses in the few patients who achieve a complete remission. However, cytokines have been largely displaced by sorafenib tosylate, sunitinib malate, and temsirolimus due to their lower rates of toxicity and positive effects on progression-free survival. Bevacizumab has also shown activity in patients with advanced disease. Estimated five-year survival rates for patients with RCC are 89.6% for localized disease, 60.8% for regional disease, and 9.5% for patients with distant metastases. Studies are currently under way to assess the activity of combinations of available agents and new targeted agents as adjuvant therapy and for the management of advanced RCC.. The options available for the management of advanced RCC have expanded considerably in the past five years with the advent of molecularly targeted therapies.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Pyrroles; Sirolimus; Stem Cell Transplantation; Sunitinib; Transplantation, Homologous

The mammalian target of rapamycin (mTOR) pathway regulates translation of key proteins that contribute to the pathogenesis of advanced hematologic malignancies. Inhibitors of mTOR (temsirolimus, everolimus, and deforolimus) constitute a new class of antitumor agents, with potential for treatment of relapsed and/or refractory hematologic malignancies. Mantle cell lymphoma (MCL) was the first hematologic malignancy in which mTOR inhibition was explored as a treatment strategy, owing to its characteristic overexpression of cyclin D1, a G1 cyclin regulated by mTOR signaling. Temsirolimus and everolimus exhibited antitumor activity against relapsed, refractory disease in phase II studies. In a randomized phase III trial, once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly was recently shown to improve progression-free survival (p=0.0009) and objective response rate (p=0.0019) versus investigator's choice of therapy in relapsed or refractory MCL. Evidence of antitumor activity seen in early clinical trials for other non-Hodgkin lymphoma subtypes, multiple myeloma, and myeloid leukemias supports further studies of mTOR inhibitors, alone or in combination strategies, in these diseases. Overall, the clinical findings to date strengthen mTOR inhibition as a novel and promising strategy for the treatment of certain hematologic malignancies, particularly for MCL.

Topics: Antineoplastic Agents; Cyclin D1; Everolimus; Hematologic Neoplasms; Humans; Intracellular Signaling Peptides and Proteins; Lymphoma, Mantle-Cell; Models, Biological; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

Surgical resection remains the cornerstone of treatment for kidney cancer. The cytokines interleukin-2 and interferon-alfa were, at one time, the only available approved systemic therapies for metastatic disease. However, the two agents are toxic when used in high doses and associated with clinical benefit for only a small subset of patients. The approval of targeted agents sunitinib, sorafenib, temsirolimus, and everolimus has offered the possibility of improved outcomes for a greater number of patients. This article reviews surgical options for metastatic renal cell carcinoma as well as clinical trial data on treatment strategies with cytokines and targeted agents.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Combined Modality Therapy; Everolimus; Humans; Indoles; Interleukin-2; Kidney Neoplasms; Neoplasm Metastasis; Nephrectomy; Niacinamide; Oncology Nursing; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Although surgery remains the primary curative treatment for renal cell carcinoma (RCC), systemic therapy also is indicated in the advanced disease setting. This article reviews the role of mammalian target of rapamycin inhibitors in the treatment of metastatic RCC. A case study is presented to illustrate side-effect management issues commonly encountered by oncology nurses in clinical practice.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Drug Eruptions; Drug Monitoring; Everolimus; Female; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Middle Aged; Oncology Nursing; Pneumonia; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

Temsirolimus, a highly specific inhibitor of mammalian target of rapamycin (mTOR), is a novel anticancer targeted therapy with a new mechanism of action. The prototype mTOR inhibitor, oral rapamycin, is poorly soluble and undergoes extensive first-pass metabolism, leading to low and potentially variable absorption and exposure. For some tumors, maximizing the bioavailability and dose intensity via intravenous (IV) administration may provide optimal clinical benefit. Temsirolimus is an ester analog of rapamycin that retains its potent intrinsic mTOR inhibitory activity while exhibiting better solubility for IV formulation. In the treatment of advanced renal cell carcinoma, temsirolimus is administered as a 30- to 60-minute IV infusion once weekly at a flat dose of 25 mg. This dosage results in high peak temsirolimus concentrations and limited immunosuppressive activity. Because temsirolimus is active and well tolerated, different dosages and schedules are being explored for other solid and hematologic malignancies, including mantle cell lymphoma. Temsirolimus exhibits a high volume of distribution that, together with IV administration, leads to extensive distribution into peripheral tissues. In addition, significant and protracted exposures are attained with sirolimus (rapamycin), the major equipotent metabolite of temsirolimus. Whereas temsirolimus and sirolimus are both metabolized by cytochrome P450 (CYP) 3A4, drug interaction studies with agents that induce or inhibit CYP3A4 activity indicate that exposure to the sirolimus metabolite is somewhat sensitive to pharmacokinetic (PK) drug interaction. Therefore, temsirolimus dose adjustments are warranted if coadministration cannot be avoided. Despite its complexity, the PK profile of IV temsirolimus is well characterized in cancer patients and provides a strong basis for its future study as a monotherapy or in combination with other anticancer agents.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug Interactions; Humans; Kidney Neoplasms; Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.73; 95% confidence interval, 0.58-0.92, P = .008) and progression-free survival (P <.001) compared with interferon alfa (IFN) for patients with poor prognostic features. Median progression-free survival durations were 3.8 and 1.9 months, respectively, for patients treated with temsirolimus or IFN, and median overall survivals were 10.9 and 7.3 months, respectively. Exploratory analyses indicate that temsirolimus benefits those patients with metastatic RCC and multiple adverse prognostic factors regardless of tumor histology or nephrectomy status. Most adverse events that occur in patients receiving temsirolimus can be managed medically (eg, hyperglycemia, hyperlipidemia) or addressed by supportive measures (eg, stomatitis, rash). Although development of symptomatic pneumonitis is rare, monitoring is recommended. Temsirolimus is now considered an important first-line treatment option for patients with advanced RCC and multiple factors predictive of short survival. Current trials are investigating the use of temsirolimus in sequence or in combination with other targeted agents to further improve outcomes.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease Progression; Humans; Kidney Neoplasms; Models, Biological; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Activation of mammalian target of rapamycin (mTOR) signaling occurs in a wide variety of human tumors and can lead to increased susceptibility to mTOR inhibitors. Temsirolimus, a novel analog of rapamycin, has shown promising preclinical and early clinical anti-tumor activity in various solid and hematologic tumor types, either alone or in combination with chemotherapy or other targeted agents. Randomized phase III trials have already demonstrated significant clinical benefits of treatment with single-agent temsirolimus in advanced renal cell carcinoma and relapsed and/or refractory mantle cell lymphoma. Other malignancies studied in the phase I and II trial settings include glioblastoma, breast cancer, endometrial cancer, non-Hodgkin lymphomas, and multiple myeloma. This article reviews a comprehensive collection of the clinical trial results reported to date for temsirolimus in various solid and hematologic malignancies, as well as current strategies being tested in ongoing trials. The findings with temsirolimus in multiple tumors provide a valuable framework for future development of temsirolimus and other mTOR inhibitors.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Hematologic Neoplasms; Humans; Neoplasms; Sirolimus

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has anti-tumor activity in patients with relapsed or refractory mantle cell lymphoma (MCL) and other mature lymphoid neoplasms. mTOR is an intracellular kinase that controls the mRNA translation of many proteins (eg, cyclin D1) that can act as oncogenes and contribute to lymphomagenesis. Characterized by overexpression of cyclin D1, MCL was identified as a disease that might be susceptible to mTOR inhibition. When single-agent temsirolimus was explored in two phase II studies for treatment of patients with relapsed or refractory MCL, it demonstrated anti-tumor activity, with overall response rates of 38% and 41%. Subsequently, a three-arm, randomized phase III trial was conducted to compare two dosing regimens of temsirolimus with investigator's choice of therapy for heavily pretreated patients with relapsed or refractory MCL (N = 162; randomized 1:1:1). Once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly (175/75) significantly improved progression-free survival (hazard ratio = 0.44; P = .0009) versus investigator's choice therapy. Median progression-free survival durations were 4.8 and 1.9 months, respectively. The objective response rates were 22% in the 175/75 group and 2% in the investigator's choice group (P = .0019). For patients receiving temsirolimus, the most frequent grade 3 or 4 adverse events were thrombocytopenia, anemia, neutropenia, and asthenia. The results of this trial established a recommended clinical dose for temsirolimus monotherapy in patients with relapsed or refractory MCL and validated the importance of mTOR in the pathogenesis of advanced MCL. Objective responses also have been reported for other mature B-cell neoplasms (eg, diffuse large B-cell lymphoma or follicular lymphoma) in the phase II setting. Temsirolimus as monotherapy or in combination with other active agents warrants further investigation for treatment of MCL and other non-Hodgkin lymphomas.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Models, Biological; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Benzamides; Benzenesulfonates; Bevacizumab; Carcinoma, Hepatocellular; Carcinoma, Renal Cell; Deoxycytidine; Drug Delivery Systems; Gastrointestinal Stromal Tumors; Gemcitabine; Humans; Imatinib Mesylate; Indoles; Neoplasms; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Piperazines; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Mantle cell lymphoma (MCL) is a unique lymphoma subtype comprising 6% to 8% of new lymphoma diagnoses. It is generally considered to be incurable with standard lymphoma therapies. The median overall survival (OS) is often reported to be 3 to 4 years, but more recent data suggest that the median OS may be longer than 5 years. There is considerable heterogeneity in MCL, with some patients succumbing to their disease in less than a year and others surviving for more than 10 years. The biology of MCL is reasonably well understood, and targeted therapies based on this knowledge are in development. Clinical trials incorporating new agents into standard therapies are under way. The optimal frontline treatment strategy is not defined and is a source of controversy. Intensive therapies administered to younger patients appear to produce better-quality remission than standard treatments, and one randomized clinical trial demonstrates improved OS with an intensive approach. Additional randomized clinical trials defining standard approaches are needed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Combined Modality Therapy; Humans; Lymphoma, Mantle-Cell; Nitrogen Mustard Compounds; Pyrazines; Radioimmunotherapy; Sirolimus; Survival Analysis; Treatment Outcome

Although recent progress has been made in the treatment of mantle cell lymphoma (MCL) the majority of patients experience relapse and ultimately die of their disease. The translocation t(11;14) is a prerequisite for the diagnosis of MCL and results in overexpression of cyclin D1. Its protein translation is controlled by mTOR, a key element of the PI3K/Akt pathway, and mTOR constitutes an attractive therapeutic target. Temsirolimus, a specific inhibitor of mTOR, has been evaluated in two Phase II trials in patients with relapsed MCL, and promising response rates up to 40% were found. Subsequently, a randomized Phase III trial was initiated, in which superiority in remission induction and progression-free survival could be demonstrated for a regimen of temsirolimus 175 mg for 3 weeks, followed by a 75-mg weekly application in comparison with established agents. This adds temsirolimus to the therapeutic armamentarium for the treatment of MCL. Further developments target combination therapy in MCL and other lymphoid neoplasms.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials as Topic; Cyclin D1; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Intracellular Signaling Peptides and Proteins; Lymphoma, Mantle-Cell; Male; Middle Aged; Remission Induction; Secondary Prevention; Sirolimus; TOR Serine-Threonine Kinases

Molecular targeted therapies represent an interesting field of pharmacological research in endometrial cancer. The loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, with consequent activation of the PI3K (phosphatidylinositol-3-kinase)-AKT (serine/threonine-specific protein kinase)-mTOR (mammalian target of rapamycin) signaling pathway, occurs in 32-83% of endometrioid-type endometrial carcinomas, thus suggesting a role for mTOR inhibition in this malignancy. Some analogues of rapamycin (CCI-799, RAD-001, AP-23573) have been developed and tested in different tumors including endometrioid-type endometrial carcinoma. For example, AP-23573 achieved a clinical benefit response in 33% of 27 heavily pretreated patients, and CCI-799 obtained a 26% partial response rate and a 63% stable disease rate in 19 patients. Overexpression of ErbB-2 (epidermal growth factor type II receptor) has been detected in 18-80% of uterine papillary serous carcinomas (UPSCs), thus providing a biological rationale for the use of trastuzumab in these aggressive tumors. UPSC often overexpresses claudin-3 and claudin-4, which represent the epithelial receptors for Clostridium perfringens enterotoxin (CPE). CPE-mediated therapy might be a novel treatment modality for UPSC resistant to chemotherapy. A better understanding of the signaling transduction pathways that are dysregulated in endometrioid-type endometrial carcinoma and UPSC will allow the development of novel molecular targeted therapies.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Endometrioid; Cystadenocarcinoma, Papillary; Drug Delivery Systems; Endometrial Neoplasms; Enterotoxins; Female; Humans; Protein Kinases; PTEN Phosphohydrolase; Receptor, ErbB-2; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Trastuzumab

Therapeutic approaches based solely on cytokine are meanwhile no longer recommended without restrictions as the primary therapy for metastatic renal cancer due to the reduced clinical response and the promising available data regarding molecular therapy. Several randomized controlled studies have been performed since the introduction of the so-called targeted therapies for metastatic renal cancer. Substantial data relevant for drug approval are available for the multikinase inhibitors sorafenib (Nexavar) and sunitinib (Sutent), the mTOR inhibitor temsirolimus (Torisel), and the monoclonal antibody bevacizumab (Avastin) in combination with interferon-alpha. Sunitinib, temsirolimus, and bevacizumab are approved for first-line treatment, whereas sorafenib was approved for second-line treatment in Germany.Clinical trials are currently investigating the questions of optimal timing, value of neoadjuvant or adjuvant treatment, form, and sequence of the molecular targeted therapy. Experimental investigations for a better understanding of signaling pathways will preferably allow preselecting patients for an individualized therapy in metastatic renal cell cancer (RCC). The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding"targeted" therapeutics during the treatment of metastatic RCC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Disease Progression; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Indoles; Kidney Neoplasms; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib; Survival Rate

To provide an overview of the current knowledge and treatment options for renal cell carcinoma (RCC).. Published articles, published abstracts, online databases, and package inserts.. Researchers have an increased understanding of the genetic and prognostic risk factors associated with RCC. Most patients with this rare type of cancer have or will develop metastasis. Nephrectomy treats localized disease and cytokine therapy was the previous standard for metastatic disease, but newly approved targeted agents, such as sorafenib, temsirolimus, and sunitinib, as well as investigational agents such as bevacizumab, are improving patient outcomes.. Understanding the biologic basis of RCC has led to therapies that are transforming the goals for treatment outcomes in patients with metastatic disease and increasing time to progression with manageable side effects.. Counseling patients and managing treatment-related side effects of therapy are critical interventions for healthcare professionals caring for patients with RCC. Evolving treatments for metastatic disease are providing better options for patients and changing disease management.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Catheter Ablation; Diffusion of Innovation; Humans; Incidence; Indoles; Interferon-alpha; Interleukin-2; Molecular Biology; Neoplasm Staging; Nephrectomy; Niacinamide; Oncology Nursing; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyridines; Pyrroles; Rare Diseases; Risk Factors; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

Temsirolimus is a specific inhibitor of mammalian target of rapamycin (mTOR) that is approved for the treatment of advanced renal cell carcinoma. mTOR is unique among antitumor drug targets because it is a convergence point for many signaling pathways. Activation of mTOR by various growth signals increases the synthesis of proteins needed for cell-cycle progression and tumor growth. Temsirolimus demonstrates a significant improvement in overall survival in patients with advanced renal cell carcinoma and poor-prognostic features, thereby validating the importance of mTOR in the natural history of this disease. mTOR might also be an important target in other tumor types, and more than 100 ongoing clinical trials are designed to identify additional malignancies that respond to temsirolimus and other mTOR inhibitors, either alone or in combination with other targeted agents or chemotherapy.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Immunosuppressive Agents; Kidney Neoplasms; Protein Kinase Inhibitors; Sirolimus; Survival Analysis

The effectiveness of multikinase inhibitors in first- and second-line therapy of metastatic renal cell carcinoma (RCC) has been evaluated in various clinical studies. Initial results indicate an increased response rate and a prolonged progression-free survival compared with cytokine-containing therapeutic approaches. The new multitargeted kinase inhibitors sorafenib (Nexavar/BAY 43-9006) and sunitinib (Sutent/SUO 11248) interfere mainly with vascular endothelial growth factor and platelet-derived growth factor pathways. Recently, temsirolimus, a specific inhibitor of mammalian target of rapamycin, demonstrated activity in RCC patients with poor prognosis. This review discusses the effectiveness of the most frequently used substances for systemically progressive RCC in consideration of the currently available clinical data.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; raf Kinases; Severity of Illness Index; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

A better understanding of renal cell carcinoma biology has led to a new era of targeted therapy in the management of metastatic renal cell carcinoma.. New phase II and phase III clinical data on both Food and Drug Administration approved and investigational targeted agents are now available, widening the choice of therapies in the treatment of metastatic renal cell carcinoma.. We provide a review of the data to facilitate effective evidence-based clinical practice and also aim to give a perspective for future clinical and translational research in renal cell carcinoma.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Temsirolimus is a targeted therapy that inhibits mammalian target of rapamycin (mTOR), a central regulator of tumor cell responses to growth stimuli. Temsirolimus has a broad anticancer activity profile that impacts tumor cell growth, proliferation, and survival through its specific inhibition of mTOR. In a randomized phase III trial that enrolled previously untreated patients with advanced renal cell carcinoma (RCC) and poor prognostic features, temsirolimus significantly prolonged overall survival compared with interferon-alpha, a standard therapy (p = 0.008). Because of the results, temsirolimus was approved by the U. S. Food and Drug Administration for treatment and is considered a first-line treatment for patients with advanced RCC with poor prognostic features. Temsirolimus is administered at a flat weekly IV dose of 25 mg given over 30-60 minutes. Gastrointestinal disorders (stomatitis, anorexia, nausea, diarrhea, and vomiting), rash, fatigue, edema, infections, and dyspnea, as well as hematologic and metabolic laboratory abnormalities occur in patients receiving temsirolimus. Metabolic side effects include hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and hypophosphatemia. Most adverse reactions associated with temsirolimus can be managed medically or addressed by supportive measures. Nurses can improve patient outcomes through early recognition of side effects and prompt interventions.

Topics: Algorithms; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Decision Trees; Drug Administration Schedule; Drug Delivery Systems; Drug Interactions; Drug Monitoring; Humans; Kidney Neoplasms; Nurse's Role; Nursing Assessment; Oncology Nursing; Patient Education as Topic; Protein Kinase Inhibitors; Protein Kinases; Randomized Controlled Trials as Topic; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases; Treatment Outcome; United States

The introduction of targeted therapy in metastatic renal cancer patients provides a whole array of individual therapeutic options. The basis for this treatment is the inactivation of the von Hippel-Lindau tumor suppressor gene, resulting in high expression of pro-angiogenic growth factors, e.g. vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). This provides the rationale for targeting these pathways in clear cell renal cell carcinomas by small molecule inhibitors. This article gives a review on clinical trials with sunitinib, sorafenib, and temsirolimus in patients with advanced renal cell carcinoma and shows how promising treatments can emerge from an understanding of the molecular genetics and signaling pathways of tumors. However, a predictive marker, e.g. specific mutations associated with drug-resistant or responsive tumors, has not yet been identified and is paramount for the future.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Drug Delivery Systems; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; Von Hippel-Lindau Tumor Suppressor Protein

Cytokine-based therapeutic approaches using interferon (IFN) and interleukin 2 (IL-2) were conventionally applied for the treatment of progressive RCC. Caused by the limited effectiveness of cytokine-based approaches in advanced renal cell carcinoma, new substances were needed. Among these, the "targeted therapies", particularly the group of the tyrosine kinase inhibitors, are of main interest. At present, multikinase inhibitors and antiangiogenic agents (VEGFR, PDGFR-beta, and mTOR) are used in first- and second-line therapies of metastatic RCC in various clinical studies. This review presents and discusses the effectiveness of the most frequently used substances in mono- or combination regimes based on current data of the ASCO 2007.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Congresses as Topic; Humans; Indoles; Kidney Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Pyrroles; Receptors, Platelet-Derived Growth Factor; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1alpha-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Female; Humans; Kidney Neoplasms; Male; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Proteins; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

Renal cell carcinoma represents nearly 3% of all cancers, predominantly affecting individuals >or=50 years of age, and until recently, few treatments options were available for metastatic disease. The 5-year median survival for these patients with metastatic renal cell carcinoma has been estimated at <10%. This review explores the data of the most relevant trials focusing on new approaches with novel agents, including sunitinib, sorafenib, bevacizumab, temsirolimus, as well as their combinations with traditional agents. We describe mechanisms of action, activity, and toxicity profile of those agents, as well as administration schedules that have been studied in clinical trials.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Delivery Systems; Female; Humans; Indoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Nephrectomy; Niacinamide; Phenylurea Compounds; Prognosis; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Survival Analysis; Treatment Outcome

Treatment of advanced renal cell carcinoma (RCC) has undergone significant changes over the past 3 years after a long period of relative stagnation. A better understanding of the biology of the tumor led to the discovery of molecular targeted therapies resulting in significant improvement in outcome for this common malignancy.. A review of new drugs, both established and investigational, at present used in the treatment of RCC is provided in this article.. A comprehensive free-text search of all available published literature including but not limited to, Medline, Scopus, American Society of Clinical Oncology presentations, National Comprehensive Cancer Network guidelines and information available through other national and international scientific organizations was carried out during the preparation of this manuscript.. Targeted therapy in RCC is a prime example of successful translational research. Continuing clinical and preclinical research in drug development holds promise for further advances in this area.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Hypoxia-inducible factor-1 (HIF-1), as a transcription factor, plays an important role in the adaptation to hypoxic microenvironment within tumors. It can induce a series of genes transcription that participate in angiogenesis, glucose metabolism, cell proliferation, and cell migration/invasion. Thus HIF-1 not only allows cancer cells to survive in hypoxic microenvironment, but also makes the tumor more aggressive. Moreover, HIF-1 also induces tumors to acquire resistance to chemo-/radio-therapy, and is related to poor prognosis. HIF-1 emerges gradually as a potential target to develop new antitumor drugs. This paper reviews recent progress in this field.

Topics: Amphotericin B; Animals; Antineoplastic Agents; Echinomycin; Humans; Hypoxia-Inducible Factor 1; Indazoles; Sirolimus; Topotecan; Transcription, Genetic

Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but only for the minority of patients, i.e. the 20% with good prognostic features. Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Several strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. New agents including the small molecule targeted inhibitors sunitinib, sorafenib and temsirolimus, and the monoclonal antibody bevacizumab have shown anti-tumour activity in randomised clinical trials and have become the standard of care for most patients. Sunitinib and temsirolimus have shown significant improvements in progression-free survival (sunitinib) and overall survival (temsirolimus) in separate phase III studies in the first-line setting when compared with interferon-alpha. Sorafenib has demonstrated prolonged progression-free survival in a phase III study in comparison with placebo in the second-line setting. More recently two phase III studies have compared bevacizumab and interferon-alpha with interferon-alpha alone. Both studies showed a statistically significant improvement in progression-free survival for the combination arm. Additional studies are needed to optimise the use of these agents by identifying those patients who most benefit and elucidating the best way of delivering them, either in combination or as sequential single agents.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Gene Targeting; Hematopoietic Stem Cell Transplantation; Humans; Indoles; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Nitrogen Mustard Compounds; Prednisone; Prognosis; Purine Nucleosides; Pyrimidinones; Risk; Rituximab; Salvage Therapy; Sirolimus; Transplantation, Autologous; Vincristine

The targeted therapies sunitinib, sorafenib, temsirolimus, and bevacizumab (when used in combination with interferon-alpha2a) have dramatically improved outcomes for patients with advanced renal cell carcinoma (RCC). Clinical application of these novel agents outside the trial setting, however, may present some challenges for treating individual patients with unique needs. In some patients, dose modifications may be considered for potential drug interactions and for management of severe cases of hematologic or nonhematologic toxicities. The more common grade 3 or 4 side effects with sunitinib and sorafenib include hypertension, fatigue, hand-foot syndrome, elevated lipase, lymphopenia, and neutropenia. Congestive heart failure is a less common but serious side effect that warrants treatment discontinuation. Temsirolimus exhibits a different side-effect profile, with the more common grade 3 or 4 side effects being metabolic in nature (i.e., elevated triglycerides, elevated glucose, hypophosphatemia) as a result of its inhibitory effects on the mammalian target of rapamycin-regulated lipid and glucose pathways. Asthenia, rash, and dyspnea also occur in patients receiving temsirolimus. Virtually all of the side effects associated with these agents can be managed effectively in the majority of patients with medical treatment or supportive interventions. Recognition and prompt management of side effects are important to avoid unnecessary dose reductions that may result in suboptimal efficacy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Indoles; Interferon alpha-2; Interferon-alpha; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Recombinant Proteins; Sirolimus; Sorafenib; Sunitinib

The mammalian target of rapamycin (mTOR) protein complex functions as an integration center for various intracellular signaling pathways involving cell cycle progression, proliferation, and angiogenesis. These pathways are frequently dysregulated in cancer, and therefore mTOR inhibition is a potentially important antitumor target. Commercially available mTOR inhibitors include rapamycin (i.e., sirolimus) and temsirolimus. Other agents under investigation include everolimus and deforolimus. mTOR inhibition has been studied in various solid tumors, including breast, gynecologic, gastrointestinal, prostate, lung, and head and neck cancers. Studies have focused on mTOR inhibition as a monotherapy or in combination with other drugs based on the principle that inhibiting as many targets as possible reduces the emergence of drug resistance. Temsirolimus is currently the only mTOR inhibitor that is specifically labeled for treatment of solid tumors. However, preclinical studies and early-phase trials are rapidly evolving. Additionally, research is further defining the complicated mTOR pathways and how they may be disordered in specific malignancies. To address these issues, NCCN convened a task force to review the underlying physiology of mTOR and related cellular pathways, and to review the current status of research of mTOR inhibition in solid tumors.

Topics: Clinical Trials as Topic; Everolimus; Humans; Neoplasms; Practice Guidelines as Topic; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Renal cell cancer (RCC) is the most common form of cancer of the kidney and accounts for approximately 44,000 cases per year in the United States. Historically, only immunotherapy showed activity in metastatic RCC. The improved survival and quality of life for patients with metastatic RCC over the last several years are direct results of advances made in understanding the development of RCC. Three targeted therapies-sunitinib, sorafenib, and temsirolimus-have been approved for use in the United States recently. Current research is aimed at developing new drugs and combining available drugs to improve upon the responses and survival seen with approved single agents.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cytotoxins; Disease-Free Survival; Drug Therapy, Combination; Everolimus; Humans; Immunosuppressive Agents; Immunotherapy; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Stem Cell Transplantation; Sunitinib; TOR Serine-Threonine Kinases; Transplantation, Homologous

Until 2006, immunotherapy (interferon-alpha or interleukin 2) was the standard medical treatment for metastatic renal cell carcinoma (RCC), and its results were disappointing: despite a few cases of complete response with prolonged survival, median survival was one year. Better understanding of the molecular mechanisms of tumor angiogenesis, especially in clear cell carcinoma, has led to the development of multiple targeted therapies to inhibit key effectors: vascular endothelial growth factor (VEGF), VEGF receptor, and mTOR (target of rapamycin). Two inhibitors targeting several protein kinases, including the VEGF receptor, have increased progression-free survival in patients with metastatic RCC and are now commercially available: sunitinib (Sutent) as first-line treatment and sorafenib (Nexavar) as second-line treatment. These targeted therapies will certainly affect overall survival, but it is too early for any firm conclusions. Their side-effects, usually low or moderate, include asthenia, anorexia, diarrhea, hand-and-foot syndrome and hypertension. Optimal management is required to ensure prolonged exposure. Other drugs have been effective: bevacizumab (Avastin), a monoclonal antibody inhibiting VEGF, increases progression-free survival as second-line treatment, and temsirolimus (Torisel), an mTOR protein kinase inhibitor, increases overall survival in the population of patients with poor prognosis. These targeted drugs will serve as the basis for development of future therapeutic strategies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Humans; Indoles; Kidney Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

To provide a systematic review of the side effects associated with sorafenib, sunitinib, and temsirolimus and to provide an outline of possible preventive or therapeutic measures.. We performed a PubMed-based systematic review of side effects associated with the three agents and relied on product monographs and prescribing information to provide an outline of treatments aimed at reducing these toxicities.. Side effects range from <1% to 72%. Grade 3/4 side effects are less common and range from <1% to 13% for sorafenib, <1% to 16% for sunitinib, and 1% to 20% for temsirolimus. Overall, sunitinib causes the most grade 3/4 side effects and sorafenib causes the fewest grade 3/4 side effects, although head-to-head trials are required to compare safety profiles of all three kinase inhibitors. Virtually all side effects can be managed effectively.. Prevention, recognition, and prompt management of side effects are of key importance and avoid unnecessary dose reductions, which may undermine treatment efficacy.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib

Antineoplastic agent-induced pulmonary toxicity is an important cause of respiratory failure. Although the incidence of antineoplastic agent-induced pulmonary toxicity seems to be low, more cases can be expected, with increasing numbers of patients receiving the new generations of antineoplastic agents. Antineoplastic agents have previously been associated with bronchospasm, hypersensitivity reactions, venous thromboembolism, and pulmonary hemorrhage. Physicians should be aware of the clinical and radiographic presentations of the pulmonary toxicities associated with the newer antineoplastic agents. The approach to diagnosis, risk factors, and possible mechanisms of antineoplastic agent-induced pulmonary toxicity are discussed in this article.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Bevacizumab; Deoxycytidine; Doxorubicin; Epirubicin; Etoposide; Everolimus; Gemcitabine; Humans; Lung; Lung Diseases; Mitoxantrone; Neoplasms; Pneumonia; Pyrimidines; Risk Factors; Sirolimus; Teniposide; Trastuzumab

Renal cell carcinoma (RCC) accounts for approximately 2% of all cancer cases worldwide. Metastatic disease is often present at the time of diagnosis of RCC and its poor response to chemotherapy and radiotherapy causes poor prognosis. Immunotherapy is relatively effective for RCC, but the response rate is approximately 15-20%. Therefore, new therapeutic approaches are necessary for these patients with metastatic RCC. Recently, the mechanisms responsible for the growth of RCC have been clarified, and molecular targeted therapy has been developed. In this paper, we review the new molecular targeted therapeutic agents effective for RCC.

Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Benzenesulfonates; Carcinoma, Renal Cell; Drug Delivery Systems; Humans; Indoles; Interferon-beta; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Liposomes; Mitochondrial Proteins; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, which plays a critical role in regulating basic cellular functions including cellular growth and proliferation. Currently, the mTOR inhibitor rapamycin and its analogues (CCI-779, RAD001, AP23573), which induce cell-cycle arrest in the G(1) phase, are being evaluated in cancer clinical trials. The mTOR inhibitors appear to be well tolerated, with skin reactions, stomatitis, myelosuppression, and metabolic abnormalities the most common toxicities seen. These adverse events are transient and reversible with interruption of dosing. Several pieces of evidence suggest a certain antitumor activity, including tumor regressions and prolonged stable disease, which has been reported among patients with a variety of malignancies, including non-small cell lung cancer (NSCLC). These promising preliminary clinical data have stimulated further research in this setting. Here, we review the basic structure of the pathway together with current results and future developments of mTOR inhibitors in the treatment of NSCLC patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Disease Progression; ErbB Receptors; Everolimus; Humans; Immunosuppressive Agents; Lung Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Temsirolimus, an ester of sirolimus (rapamycin), selectively inhibits the kinase mammalian target of rapamycin and consequently blocks the translation of cell cycle regulatory proteins and prevents the over expression of angiogenic growth factors. Patients with advanced renal cell carcinoma and a poor prognosis who received a once-weekly intravenous infusion of temsirolimus 25 mg experienced significant survival benefits compared with patients receiving standard interferon-alpha (IFNalpha) therapy (3-18 MU subcutaneously three times weekly) in a large phase III clinical study. Median overall survival was 10.9 versus 7.3 months, progression-free survival was 5.5 versus 3.1 months. Objective response rates were 8.6% in temsirolimus recipients versus 4.8% in IFNalpha recipients. Temsirolimus monotherapy recipients experienced significantly fewer grade 3 or 4 adverse events and had numerically fewer withdrawals for adverse events than patients receiving IFNalpha.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Randomized Controlled Trials as Topic; Sirolimus

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Immunotherapy; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

The recent contributions to renal cell carcinoma in the fields of molecular biology and the expanded use of molecularly targeted agents will be reviewed. This study is intended to update prognostic and therapeutic decision-making data and provide perspective on advances in understanding the molecular biology of this disease.. Updates to the currently used prognostic algorithms for renal cell carcinoma are needed, and recently verified prognostic nomograms will be discussed. This comes in the wake of numerous advances in the use of molecularly targeted drugs, which will be reviewed. Finally, advancements in understanding the biology of renal cell carcinoma include the discovery of von Hippel-Lindau associated mechanisms involved in renal cyst formation and renewed appreciation for the influence of this pathway on the tumor cell glucose utilization profile.. Renal cell carcinoma continues to evolve swiftly with the approval of new agents and the maturation of clinical trials to provide relevant structure to treatment decisions. This study will give an overview of the latest concepts in the epidemiology and biology of renal cell carcinoma and provide current surgical and systemic updates for managing renal cell carcinoma.

Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Mutation; Niacinamide; Nomograms; Phenylurea Compounds; Prognosis; Pyridines; Sirolimus; Sorafenib; Vascular Endothelial Growth Factor A; von Hippel-Lindau Disease

Metastatic renal cell carcinoma (RCC) has a poor overall survival. Localized RCC remains a surgical disease. About 20%-30% patients who present with limited disease at the time of nephrectomy develop metastasis. The median time to relapse after nephrectomy is 15-18 months. The maximum numbers of relapses are within the first 3 years. In metastatic RCC, immunotherapy is effective in a relatively small percentage of patients but is very toxic. In recent years, there has been an improved understanding of the biology of RCC. This has lead to the development of various agents that target ligands at the molecular level. The hypoxia inducible factor-alfa (HIF-)/ vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR) signal transduction pathway are targets for some of these novel agents. Recent randomized phase III trials have shown an improved outcome in patients with metastatic disease who received these targeted agents. This review deals with management of advanced and metastatic renal cell cancer with an emphasis on recently developed targeted therapies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Graft vs Host Disease; Humans; Immunologic Factors; Indoles; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Multivariate Analysis; Niacinamide; Phenylurea Compounds; Prognosis; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Risk Assessment; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

The mammalian target of rapamycin (mTOR) is a large and highly conserved kinase that integrates growth factor stimulation, energy and nutrient availability to modulate translation of proteins responsible for cellular growth and proliferation. Its importance in malignant cells provides strong rationale for the development of mTOR inhibitors (mTORi) in a broad variety of solid tumors and hematological malignancies. However several questions regarding mTOR biology and its interaction with pharmacological inhibitors remain unanswered and are relevant for further development of this novel family of cancer drugs. Nevertheless, mTORi have demonstrated activity in lymphoma cells either alone or in combination with cytotoxic agents. The most promising results have been seen in mantle cell lymphoma (MCL), likely because of its dependence on Cyclin D, the translation of which is largely regulated by mTOR activity. The currently knowledge of mTOR biology will here be reviewed along with the status of clinical development of mTORi in non-Hodgkin's lymphomas.

Topics: Antibiotics, Antineoplastic; Cyclin D1; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Management of renal cell carcinoma (RCC) has made considerable progress in recent years, and new emerging strategies are being developed. On the basis of the results of two randomised studies in the early 2000s, nephrectomy has now become the standard as cytoreductive surgery before embarking on systemic treatment with cytokines. Interleukin (IL)-2 and interferon were the standard treatment in metastatic RCC (MRCC) until 2006. The efficacy of these two drugs, which have now been used for >20 years in MRCC, is still controversial. On the basis of many studies, these drugs should not be given to patients with a poor prognosis. In patients with good prognostic factors, a cytokine-based regimen should remain the standard as either a high-dose IL-2 or subcutaneous regimen. In patients with intermediate risk, the results of the French Percy Quattro study encourage the use of new targeted therapies as first-line therapy. Development of targeted therapies in RCC has been necessary largely because the Von Hippel-Lindau (VHL) gene is often mutated in sporadic RCC. VHL protein abnormalities lead to accumulation of hypoxia-inducible factor (HIF)-alpha and activation of a series of genes, including vascular endothelial growth factor (VEGF), thus inducing angiogenesis. Results from many recent studies with new agents that block the VEGF pathway have been reported and offer new strategic options for patients with MRCC. Sunitinib and sorafenib, two tyrosine kinase inhibitors, improve progression-free survival in RCC compared with standard treatment and have been recently approved. Temsirolimus, a mammalian target of rapamycin inhibitor regulating HIF-alpha, improves survival in RCC patients with poor risk features. Bevacizumab, a monoclonal antibody against VEGF, has shown very promising efficacy. Overall, treatment of MRCC is currently moving from the cytokine era to the targeted agent era. However, many questions still remain regarding the efficacy of combination treatments and on the best way to achieve complete remission, which is probably the best hope of curing MRCC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Nephrectomy; Protein-Tyrosine Kinases; Sirolimus; Treatment Outcome

Bone and soft tissue sarcomas represent rare tumors that can be cured by local treatment at early stages of disease. However, advanced or metastatic disease is rarely cured, and very few drugs have shown efficacy in this setting. Early studies with mTOR inhibitors have demonstrated antitumor activity in patients with metastatic sarcoma who failed previous chemotherapies. The response rate and durable stable disease in early studies, as well as the tolerability profile, recommend these drugs as promising candidates for further clinical studies. This article discusses preliminary results from clinical trials in patients with advanced or metastatic sarcoma as well as future perspectives.

Topics: Antineoplastic Agents; Bone Neoplasms; Drug Therapy, Combination; Everolimus; Gastrointestinal Stromal Tumors; Humans; Protein Kinase Inhibitors; Protein Kinases; Sarcoma; Sirolimus; Soft Tissue Neoplasms; TOR Serine-Threonine Kinases

Renal cell carcinoma (RCC) is a highly vascular tumor in which a growing understanding of disease biology has been translated into clinically active systemic therapies. The most clinically developed targeted therapies in advanced RCC are those that target the vascular endothelial growth factor (VEGF) ligand or receptor (VEGFR) and therapy directed against the mammalian target of rapamycin (mTOR). Sutent and sorafenib are orally available inhibitors of the VEGFR and platelet derived growth factor receptor (PDGFR). Temsirolimus is an mTOR inhibitor that leads to G1 cell cycle arrest and may affect VEGF production. This article briefly describes the biological pathways involved in the development of RCC and the results of clinical trials using targeted therapy in metastatic RCC.

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Delivery Systems; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Humans; Kidney Neoplasms; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Sirolimus; Treatment Outcome

Sporadic renal cell carcinomas are characterized by EGFR (HER-1) and EGFR-2 (HER-2) expression, however, signal transduction inhibitors of this pathway were clinically ineffective. Clear cell renal cell cancer is hormone-, irradiation- and chemotherapy resistant with moderate sensitivity to immunotherapy. The only clinically effective class of agents in case of this tumor type was proved to be the angiosuppressive agents. In 2005 FDA approved sorafenib for the first line treatment while in 2006 sunitinib for second line treatment in the cytokine resistant medium-risk renal cell carcinoma. This was followed by the European approval of both agents for second line treatment of renal cell cancer. Sunitinib was approved for first line treatment of renal cell cancer in Europe based on a phase III trial comparing it to interferon. Temsirolimus obtained its approval for the treatment of high risk renal cell cancer patients in 2007. Last but not least, FDA approval is on the way in case of bevacizumab as well to treat renal cell cancer. Based on the data demonstrated on the ASCO'2007, various modalities have to be developed for various stages of progression of clear cell renal cell cancer.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Indoles; Interferon-alpha; Kidney Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Protein Kinases; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; Vascular Endothelial Growth Factor A

The molecular target of rapamycin (mTOR) is central to a complex intracellular signaling pathway and is involved in diverse processes including cell growth and proliferation, angiogenesis, autophagy, and metabolism. Although sirolimus (rapamycin), the oldest inhibitor of mTOR, was discovered more than 30 years ago, renewed interest in this pathway is evident by the numerous rapalogs recently developed. These newer agents borrow from the structure of sirolimus and, although there are some pharmacokinetic differences, they appear to differ little in terms of pharmacodynamic effects and overall tolerability. Given the multitude of potential applications for this class of agents and the decrease in cost that can be expected upon the expiration of sirolimus patents, renewed focus on this agent is warranted.

Topics: Animals; Antifungal Agents; Antineoplastic Agents; Drug Design; Drug Interactions; Everolimus; Humans; Immunosuppressive Agents; Molecular Structure; Protein Kinases; Signal Transduction; Sirolimus; Structure-Activity Relationship; TOR Serine-Threonine Kinases

Cytokine therapies have been the standard of care in metastatic renal cell carcinoma (RCC). However, these agents only provide clinical benefit to a small subset of patients and are associated with significant toxicity. A better understanding of the molecular biology of RCC has identified the vascular endothelial growth factor (VEGF) and platelet-derived growth factor signalling pathways as rational targets for anticancer therapy. The multitargeted receptor tyrosine kinase inhibitors sunitinib and sorafenib have both demonstrated improved efficacy as second-line therapy in patients with RCC. Sunitinib has also been shown to be effective in the first-line setting, and has recently received European Union approval as first-line treatment for advanced and/or metastatic RCC. There is also recent evidence that temsirolimus (an inhibitor of the mammalian target of rapamycin) and bevacizumab (a mAb targeted against VEGF) may provide benefits in the first-line treatment setting. These results confirm that inhibiting these tumour targets is a feasible approach to treatment and provides a more positive outlook for the future management of metastatic RCC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cytokines; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been found in many human tumors and implicated in the promotion of cancer cell growth and survival. Hence, the mTOR pathway is considered an important target for anticancer drug development. Currently, the mTOR inhibitor rapamycin and its derivatives CCI-779, RAD001, and AP23573 are being evaluated in cancer clinical trials. To date, clinical results have shown good tolerability of treatment with mTOR inhibitors in most reports and varying effectiveness of mTOR inhibitors in a variety of tumors in a subset of patients. For the targeted treatment of sarcomas, AP23573 has shown promising clinical efficacy and low toxicity profiles in patients. Further studies should define the optimal dose/schedule, patient selection, and combination strategies with other biological agents, especially those targeting signaling pathways crucial for cell survival. Disclosure of potential conflicts of interest is found at the end of this article.

Topics: Clinical Trials as Topic; Everolimus; Humans; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases

Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. Sorafenib and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC.

Topics: Angiogenesis Inhibitors; Benzenesulfonates; Biomarkers, Tumor; Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Everolimus; Humans; Indoles; Kidney Neoplasms; Niacinamide; Patient Selection; Phenylurea Compounds; Practice Guidelines as Topic; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Pyrroles; Receptor, Platelet-Derived Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome

Angiogenesis targeting with inhibitors of VEGF receptors is currently modifying in depth the treatment strategy of metastatic clear cell renal carcinoma. Although immunotherapy remains prescribed in selected patients with good prognosis, sunitinib and sorafenib are presently the most active agents in this malignancy. The results available, in terms of response as in terms of progression-free survival, argue in favour of the use of sunitinib in first line. The two agents have distinct toxicity profiles, which may lead in the future to select the treatment as a function of an individual patient basis. Preliminary results suggest the possibility of partial cross-resistance between them.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib

Temsirolimus (CCI-779), a small molecule inhibitor of mTOR protein, is a water-soluble synthetic rapamycin ester that has been developed in both oral and intravenous (i.v.) formulations. PI3k/Akt/mTOR pathway activation is implicated in the pathogenesis of many cancers. Inhibition of mTOR protein abrogates pathway-mediated cellular transcription and translation, leading to cell cycle arrest, antiangiogenesis and apoptosis. The drug has significant in vitro antitumor effect against a number of cancer cell lines and has demonstrated in vivo cytostatic activity in xenograft models. Flat dosing of 25 mg, 75 mg and 250 mg i.v. weekly were selected for tumor-specific phase I trials. Biological activity was observed at all these doses. However, the frequency and intensity of the toxicities increased at higher doses and more high-dose patients had to reduce the dose or discontinue the drug. Notable temsirolimus-related toxicities include rash, mucostomatitis, diarrhea, hyperlipidemia, hyperglycemia and thrombocytopenia. Temsirolimus is farther along in clinical development than any other mTOR inhibitor in its class and has demonstrated significant activity in patients with poor-risk clear-cell renal cell carcinoma. Patients receiving temsirolimus alone achieved longer survival than those receiving interferon alone or temsirolimus plus interferon in a randomized phase III trial. Predictive biomarkers for clinical efficacy are undetermined and remain under investigation.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Delivery Systems; Humans; Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) is a protein kinase that plays a pivotal role in the control of cell growth and development. A part of the PI3K/Akt pathway, mTOR responds to growth factor stimuli as well as nutrient availability by variations in downstream phosphorylation. Increasing knowledge of the upstream regulators and downstream targets of mTOR has led to the development of anticancer drugs that suppress protein synthesis and metabolism. Rapamycin (sirolimus) and three rapamycin analogues are currently being evaluated in clinical trials: temsirolimus (CCI-779, Wyeth), everolimus (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals Inc.). This review will highlight the role of these inhibitors in the treatment of sarcoma.

Topics: Clinical Trials as Topic; Enzyme Inhibitors; Everolimus; Humans; Protein Kinases; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases

Mammalian target of rapamycin (mTOR) is a key downstream molecule of PI3K/Akt pathway. It integrates input signals from growth factors, nutrients and energy to regulate cell growth and proliferation via different cellular processes. Gene mutations of mTOR pathway-related proteins are very common in many carcinomas. Abnormal expression of these related proteins can result in aberrant hyperactivity of mTOR pathway. Therefore, mTOR-targeted therapy has shown promising role in the management of various cancers. This article reviewed the current status of researches on mTOR and its inhibitors in antitumor therapy.

Topics: Animals; Antineoplastic Agents; Everolimus; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) kinase is positioned at the juncture of several pathways regulating cell growth and proliferation. It is the downstream effector of the oncogenic PI3K/Akt pathway and is a key regulator of translational initiation. Accumulating data support mTOR's role in lymphomagenesis, and its inhibition in preclinical models leads to lymphoma regression. The rationale for testing mTOR inhibitors in patients with lymphoma is evident, and early clinical data is promising. Along with the prototype of mTOR inhibitors, rapamycin, there are three mTOR inhibitors furthest along in development: temsirolimus, everolimus, and AP23573. These agents are emerging as well-tolerated drugs with encouraging preliminary activity. Here we review the rationale for testing mTOR inhibitors in lymphoma, the phase 1 trials influencing dose and schedule of mTOR inhibitors, and summarize the clinical results in obtained to date in patients with lymphoma.

Topics: Antineoplastic Agents; Everolimus; Humans; Lymphoma; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Recent successes using Gleevec for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors have provided proof that strategies to target signal transduction pathways mutated in human cancers can work. However, the application of this strategy to other cancers has been slow. Central to alleviating this impedance is the molecular characterization of the tumors. There is an urgent need to translate basic scientific findings into relevant, clinically applicable molecular diagnostic assays.

Topics: Animals; Biomarkers, Tumor; Clinical Trials as Topic; Humans; Kidney Neoplasms; Models, Biological; Neoplasms; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The standard treatment for renal cell carcinoma (RCC) is surgery. Partial nephrectomy is often performed for treatment of small RCC. Radiofrequency ablation (RFA) offers another nephron-sparing minimally invasive approach. It is most successful for tumors not larger than 3 cm in diameter. The rate of severe complications of RFA is low. Further studies are necessary to determine the long-term efficacy of RFA in RCC. Metastatic RCC is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients. New therapies such as targeted molecular therapies are being developed to improve efficacy and treat those patients who are resistant to systemic immunotherapy. Targeted molecular therapies include inhibition of the Raf kinase pathway, inhibition of its receptor kinases, anti-vascular endothelial growth factor monoclonal antibody or the mammalian target of rapamycin pathway. Further clinical research will be required to develop a more effective therapy and the application of combined treatment modalities.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Catheter Ablation; Combined Modality Therapy; Female; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Male; Minimally Invasive Surgical Procedures; Nephrectomy; Niacinamide; Phenylurea Compounds; Prognosis; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Topics: Antibiotics, Antineoplastic; Clinical Trials, Phase II as Topic; Drug Design; Enzyme Inhibitors; Female; Humans; Male; Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) is a threonine kinase involved in intracellular pro-survival signaling. Its activation leads to progression from the G1 to S phase of the cell cycle. Constitutive activation of the mTOR-related messengers, including phosphatidylinositol 3-kinase, Akt kinase, ribosomal p70S6 kinase and eukaryotic translation initiation factor 4E-binding protein kinase, was found in numerous malignancies. Recent data indicate that the mTOR kinase pathway can be an attractive target for anti-cancer drug development. A well-known mTOR inhibitor is rapamycin (RAPA), previously applied as an immunosuppressive agent in transplant studies. Recently, analogs of RAPA, such as CCI-779, RAD001 and AP23573, have been developed. All of those agents are currently being tested in patients with solid or hematological tumors in several clinical trials. This review presents recent developments in targeting the mTOR kinase pathway.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Design; Enzyme Activation; Everolimus; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Sarcomas are a rare malignancy accounting for less than 1% of all cancers diagnosed annually. Standard chemotherapy has a response rate of around 25% and newer agents are needed to improve the outcome in patients with advanced sarcomas. The mammalian target of rapamycin plays a central role in cell growth, proliferation, and apoptosis and its inhibition has demonstrated antitumor activity in many tumors and shows promise against sarcomas.. Recent studies of mammalian target of rapamycin inhibitors in sarcomas have demonstrated clinical benefit response in sarcomas.. Clinical benefit response uses standard Response Evaluation Criteria in Solid Tumors of complete response and partial response as well as stable disease lasting at least 4 months as an endpoint. This endpoint has been shown to select promising new agents against sarcomas. Using this endpoint, the use of the mammalian target of rapamycin inhibitor AP23573 has demonstrated activity against sarcomas. The use of the inhibitor RAD001 (everolimus) along with imatinib in patients with imatinib resistant gastrointestinal stromal tumor has shown promise. Future studies will need to be performed to determine the clinical differences among the mammalian target of rapamycin inhibitors in different subsets of sarcomas.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Clinical Trials as Topic; Humans; Positron-Emission Tomography; Protein Kinase Inhibitors; Protein Kinases; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Autophagy is one of the intracellular systems that is responsible for protein trafficking (degradation/recycling) in eukaryotic cells. This ubiquitous process contributes to cytosolic homeostasis, but its deregulation is often associated with various pathologies, including neurodegenerative diseases and cancer and pathologies with an altered inflammatory response. This review provides an overview of autophagy and discusses its regulation, function and future therapeutic possibilities, with a focus on the role of autophagy in inflammation.

Topics: Animals; Apoptosis; Autophagy; Bacterial Infections; Homeostasis; Humans; Inflammation; Lysosomes; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Proteins; Sirolimus; Stress, Physiological; Virus Diseases

The mammalian target of rapamycin (mTOR) is involved in the control of cellular growth and proliferation. Abnormal activation of signaling pathways both proximal and distal to this kinase occurs frequently in human cancer, suggesting that mTOR is an attractive target for antineoplastic therapies. Rapamycin and its analogs inhibit mTOR and have demonstrated potent antitumor activity in vitro and in xenograft models. Several phase I and phase II clinical studies with rapamycin-like drugs have been conducted and have demonstrated antitumor activity in various types of refractory neoplasms. To date, mTOR inhibitors have been well tolerated at a wide range of doses, making the selection of phase II trial doses-based solely on toxicity criteria difficult. Assessment of the pharmacodynamic effects in surrogate tumor tissues has been used to determine the pharmacodynamically active doses. The lack of a parallel assessment of tumor tissue effects coupled with the intrinsically high interpatient variability has limited the value of these studies. A better understanding of markers that are predictive of response to mTOR inhibitors could be used for improved patient selection in clinical trials. mTOR inhibitors are promising anticancer agents; however, further studies are required to advance these drugs into the clinic. This review will describe the mTOR pathway and highlight its role as a potential drug target. Several mTOR inhibitors that are currently undergoing clinical development, and the challenges facing the development of inhibitors of this type, will also be discussed.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Everolimus; Humans; Neoplasms; Prodrugs; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Systemic therapy for breast cancer is undergoing many interesting advances. In recent years, a better understanding of the underlying biology of cancer has led to the identification of several opportunities to target cellular pathways for therapeutic advantage. Hormonal therapy is often chosen as the first line of therapy because it is generally very well tolerated. However, most patients eventually become unresponsive to endocrine manipulation. Improved understanding of the mechanisms of hormonal resistance, and of the interplay between hormone receptors and cellular growth pathways, provides the rationale for combining signal transduction inhibitors and hormonal agents to overcome resistance. Emerging data from preclinical studies suggest that this goal might be achievable in the clinic. Antiangiogenic therapy has shown efficacy in colorectal and lung cancer and appears promising in breast cancer, although improved overall survival has not yet been shown. There have also been advances in cytotoxic chemotherapy. Reformulation of paclitaxel in polyoxy-castor-oil-free albumin nanoparticles (ABI-007) has allowed more convenient, safer, and enhanced drug delivery with associated improvement in outcomes. New agents with novel mechanisms of action are also in development and appear to have activity in cancer cells that are resistant to currently available agents.

Topics: Angiogenesis Inhibitors; Aromatase Inhibitors; Breast Neoplasms; ErbB Receptors; Estradiol; Female; Fulvestrant; Humans; MAP Kinase Signaling System; Paclitaxel; Sirolimus; Vinblastine

Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, significant advances in understanding the molecular mechanisms underlying RCC have led to the development of rationally designed therapies, which are now being tested clinically. To date, the vascular endothelial growth factor receptor (VEGFR) pathway has been the most promising target, and two agents (BAY 43-9006 and SU 11248) that inhibit not only VEGFR but also other receptors, including platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT3), KIT, and Raf kinase, were recently approved by the FDA for advanced RCC. In addition, a phase III trial investigating the addition of VEGF inhibition to interferon alpha (IFN-alpha) in RCC is also now going on. Although the clinical activity of existing agents is to be further defined in ongoing trials, the exciting clinical response data with VEGF inhibition in RCC have demonstrated a key role in the treatment of this historically resistant malignancy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib

Recent developments in the understanding of the molecular biology of renal cell carcinoma have led to the development of several biologic agents with different mechanisms of action. In 2005, promising results have been observed especially in second-line therapy following cytokine failures and in 2006 more mature data with regard to time to progression and overall survival should be available. This review, analyzing basic translational research principles, will summarize the available evidence with a glimpse of the future therapeutic approaches in renal cell carcinoma.. Vascular endothelial growth factor- and platelet-derived growth factor receptor-inhibiting drugs (SU11248, Bay 43-9006, Bevacizumab, AG-013736, etc.) report time to progression ranging between 4 and 9 months and variable benefits in overall survival. Confirmatory studies are ongoing regarding other novel treatments (CCI-779, Infliximab, PTK-787).. In renal cell carcinoma, there is a strong rationale for targeting multiple pathways and particularly angiogenesis. Vascular endothelial growth factor- and platelet-derived growth factor receptor-inhibiting drugs have been rapidly approved in the second-line setting and will soon be used as first-line therapy. In the next years, translational/clinical research will provide evidence for combination strategies to improve upon the results of the biologic agents and hopefully offer more hope to patients with renal cell carcinoma.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Erlotinib Hydrochloride; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

Topics: Antibiotics, Antineoplastic; Clinical Trials as Topic; Everolimus; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Recent developments in molecular biology have lead to an increased understanding of the events involved in renal cell carcinoma (RCC) carcinogenesis. In this field, basic molecular pathways important to oncogenic transformation secondary to Von Hippel-Lindau (VHL) tumor suppression gene inactivation, associated to clear-cell RCC, have been elucidated. Loss of function of VHL results in the high-expression of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). New therapies against specific targets in RCC have demonstrated significant clinical activity in patients. These therapeutic approaches are based on the VEGF inhibition by using anti-VEGF monoclonal antibodies (bevacizumab) or multi-kinase inhibitors, that also target PDGF and c-kit tyrosine kinases (sorafenib, sunitinib); or by the inhibition of the mammalian target of rapamycin (mTOR) pathway (temsirolimus). This article reviews current knowledge of molecular pathogenesis of inherited and sporadic RCC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Exons; Humans; Indoles; Kidney Neoplasms; Molecular Biology; Mutation; Niacinamide; Phenylurea Compounds; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Pyridines; Pyrroles; raf Kinases; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A; von Hippel-Lindau Disease

Temsirolimus (CCI779), an intravenous analog of rapamycin, presents immunosuppressive properties and also antiproliferative activity. Its principal target is the mTOR serine/threonin kinase which controls the initiation of the transcription of many ARNm implicated in carcinogenesis. Breast cancers, glioblastoma and renal cell carcinoma were particularly studied with response rates from 10 to 20 %. In haematology, mantle-cell lymphoma is of particular interest because of constitutional activation of cyclin D1 (response rate of 40 %). As a whole these data define temsirolimus as a promising new drug. Current and further developments are based on its association with chemotherapy in a concomitant or sequential way.

Topics: Antineoplastic Agents; Breast Neoplasms; Cyclin D1; Glioblastoma; Humans; Kidney Neoplasms; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

The discovery of a relationship for the VHL tumor suppressor gene, hypoxia inducible factor-1 alpha, and vascular endothelial growth factor in the growth of clear-cell renal cell carcinoma (RCC) has identified a pathway for novel targeted therapy. This study evaluated the impact of these agents on metastatic RCC (mRCC), and highlights recent phase II and III trials. A systematic review examined the clinical data for novel targeted agents in mRCC, with a focus on randomized phase II and III trials of the novel targeted agents sunitinib, temsirolimus, sorafenib, and bevacizumab. Several agents, including the small-molecule targeted inhibitors sunitinib, temsirolimus, sorafenib, and the monoclonal antibody bevacizumab, have demonstrated antitumor activity in randomized trials. Superior activity was found with sunitinib and temsirolimus versus cytokines in first-line therapy. Improved progression-free survival was reported with sorafenib and bevacizumab given second-line compared with placebo. Targeted therapies show promising activity in this disease, and they have been changing patient management. Sunitinib and sorafenib were recently approved by the US Food and Drug Administration for treatment of mRCC, These drugs are currently included in clinical practice.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib; Von Hippel-Lindau Tumor Suppressor Protein

The angiogenic phenotype of renal cell carcinoma results from vascular endothelial growth factor pathway activation. Several different strategies targeting various aspects of the pathway have emerged as clinically relevant therapeutics in metastatic renal cell carcinoma. Key clinical data regarding these approaches are presented in this article. Furthermore, there are several considerations as to the further development of these agents and their appropriate application in metastatic renal cell carcinoma, such as timing of therapy, choice of initial therapy, continued role of debulking nephrectomy and toxicity concerns. These issues are discussed in light of current data and strategies for further drug development are presented.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Case Management; Clinical Trials as Topic; Combined Modality Therapy; Cytokines; Humans; Indoles; Kidney Neoplasms; Neovascularization, Pathologic; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome; Vascular Endothelial Growth Factor A

The year 2006 will mark a turning point in the daily management of patients with metastatic renal cell carcinoma. The impact of immunotherapy with interferon-alpha or interleukin-2 has been shown to be restricted to a minority of patients. The growing understanding of molecular mechanisms involved in the pathogenesis of the disease, especially clear-cell carcinoma, has led to the development of multiple targeted therapies with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of the vascular endothelial growth factor receptor have been shown to improve the progression-free survival of patients in first- (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, an agent that inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Drug Delivery Systems; Drug Therapy, Combination; Forecasting; Humans; Immunologic Factors; Immunotherapy; Indoles; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Neoplasm Proteins; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases

Inheritance of a defective copy of the von Hippel-Lindau (VHL) gene leads to the most common cause of inherited renal cell carcinoma (RCC). In addition, most patients with sporadic RCC have aberrant VHL. In the absence of VHL, hypoxia-inducible factor alpha accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. We review here the biology of RCC and how a combination of proximal and distal block of VHL/hypoxia-inducible factor alpha pathway by novel targeted agents, including sunitinib, sorafenib, bevacizumab, everolimus, and temsirolimus, has led to significant improvements in progression-free survival.

Topics: Benzenesulfonates; Biomedical Research; Carcinoma, Renal Cell; Enzyme Inhibitors; Everolimus; Humans; Indoles; Kidney Neoplasms; Models, Biological; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; Von Hippel-Lindau Tumor Suppressor Protein

Glioblastoma, the most highly aggressive and lethal form of brain cancer, has been a particular challenge to treat in terms of improving a patient's quality of life and outcome. Each of the current treatment options is limited due to factors intrinsic to the tumor's biology and the special microenvironment of its location within the brain. Surgical resection is limited by the non-circumscribed borders that can be detected. Radiation therapy has to contend with neurotoxicity to adjacent normal tissues. Chemotherapy is constrained by the blood-brain barrier, which is a very real constraint of systemic therapy -- producing minimal benefit with substantial toxicity in order to administer therapeutic dosages. In part, such hurdles explain the reasons why survival has changed little over many decades of research in this field. The newest generation of treatments includes more effective cytotoxic agents, so-called targeted compounds, and biologics/immunotherapeutics. This article summarizes the preclinical proof-of-concept research and human studies involving some of the agents creating the most positive buzz in the medical community. The advantages and limitations of each are described.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Benzamides; Biocompatible Materials; Brain Neoplasms; Cancer Vaccines; Clinical Trials as Topic; Combined Modality Therapy; Dacarbazine; Decanoic Acids; ErbB Receptors; Erlotinib Hydrochloride; Farnesyltranstransferase; Gefitinib; Glioblastoma; Humans; Imatinib Mesylate; Immunotoxins; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Piperazines; Polyesters; Protein Kinase Inhibitors; Proteins; Pyrimidines; Quinazolines; Sirolimus; Temozolomide; TOR Serine-Threonine Kinases; Transcription Factors

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Genetic Markers; Humans; Intracellular Signaling Peptides and Proteins; Patient Selection; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.

Topics: Everolimus; Hematologic Neoplasms; Humans; Leukemia; Protein Kinases; Sirolimus; Substrate Specificity; TOR Serine-Threonine Kinases

The scientific rationale and existing evidence for the use of novel molecular targets in the chemoprevention of cancer are reviewed, with special attention to prostate cancer.. A search for relevant literature on basic science and clinical trials was conducted using PubMed/MEDLINE.. The emergence of molecularly targeted therapies for advanced malignancies creates an important opportunity to examine these agents for the chemoprevention of prostate cancer. Two critical targets in the proliferation and malignant transformation of normal cells, the PI3/Akt signal transduction pathway and the epidermal growth factor receptor, are currently the focus of several novel investigational therapies that are in late stage phase II and phase III studies.. Research to date supports consideration of these novel molecular targets as future agents in the chemoprevention of prostate cancer.

Topics: Anticarcinogenic Agents; ErbB Receptors; Humans; Male; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway, which mediates cell survival and proliferation. mTOR regulates essential signal-transduction pathways, is involved in the coupling of growth stimuli with cell cycle progression, and initiates mRNA translation in response to favorable nutrient environments. mTOR is involved in regulating many aspects of cell growth, including membrane traffic, protein degradation, protein kinase C signaling, ribosome biogenesis, and transcription. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein 1, its inhibitors cause G1-phase cell cycle arrest. Inhibitors of mTOR also prevent cyclin dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause G1-phase arrest. It is known that the phosphatase and tensin homologue tumor suppressor gene (PTEN) plays a major role in embryonic development, cell migration, and apoptosis. Malignancies with PTEN mutations, which are associated with constitutive activation of the PI3K/Akt pathway, are relatively resistant to apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin analogs with relatively favorable pharmaceutical properties, including CCI-779, RAD001, and AP23573, are under investigation in patients with hematologic malignancies.

Topics: Apoptosis; Cell Division; Cell Survival; Cyclin-Dependent Kinases; Enzyme Activation; Everolimus; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Germ-Line Mutation; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Phosphoric Monoester Hydrolases; Protein Kinases; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

Endocrine therapy is the most effective systemic treatment for patients with hormone-receptor-positive (HR(+)) breast cancer. Unfortunately, efficacy is often limited by the onset of resistance, which is almost inevitable for patients with advanced disease. Several patterns of endocrine resistance are recognizable clinically, including: A) tumors that are inherently insensitive to all attempts at estrogen receptor (ER) targeting despite expression of ER (pan-endocrine therapy resistance); B) tumors that are estrogen dependent but resistant to one or more specific endocrine therapies (agent-selective resistance); and C) tumors that initially respond but subsequently progress (acquired resistance). Current insights into the molecular basis for these resistance patterns are rudimentary, but are most clearly illuminated by investigations that focus on the crosstalk between the ErbB or HER peptide growth factor family and the ER. The data are sufficiently compelling to be addressed by ongoing clinical trials that examine combinations of endocrine agents and either trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) or ErbB-specific tyrosine kinase (TK) inhibitors. Preliminary data from a small "proof of concept" phase II study of letrozole (Femara; Novartis Pharmaceuticals Corporation; East Hanover, NJ) and trastuzumab demonstrated durable responses despite tamoxifen (Nolvadex; AstraZeneca Pharmaceuticals; Wilmington, DE) resistance. Efficacy was variable, however, despite the selection of patients on the basis of ER and ErbB-2 coexpression. Complicating matters further, resistance often occurs in the absence of any evidence for ErbB TK family member expression. In the absence of a clear target, common downstream signal transduction proteins that are known to intersect with the ER pathway can be inhibited to address resistance, including G proteins with farnesyltransferase inhibitors and molecular target of rapamycin (mTOR) with rapamycin analogues. With a number of phase III clinical trials now under way, major advances in the endocrine treatment of advanced disease are possible.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Farnesyltranstransferase; Humans; Immunosuppressive Agents; Letrozole; Nitriles; Receptor, ErbB-2; Receptors, Estrogen; Sirolimus; Tamoxifen; Triazoles

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biologic functions such as transcriptional and translational control. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. In breast cancer this pathway can be activated by membrane receptors, including the HER (or ErbB) family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. There is evidence suggesting that Akt promotes breast cancer cell survival and resistance to chemotherapy, trastuzumab, and tamoxifen. Rapamycin is a specific mTOR antagonist that targets this pathway and blocks the downstream signaling elements, resulting in cell cycle arrest in the G1 phase. Targeting the Akt/PI3K pathway with mTOR antagonists may increase the therapeutic efficacy of breast cancer therapy.

Topics: Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Cell Cycle; Humans; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Wyeth (formerly American Home Products) is developing temsirolimus [Cell cycle inhibitor-779, CCI 779], an ester analogue of sirolimus, for the treatment of cancer, multiple sclerosis and rheumatoid arthritis. Temsirolimus binds to the cytosolic protein, FKBP, which subsequently inhibits mTOR (mammalian target of rapamycin). Inhibition of mTOR blocks a number of signal transduction pathways that suppress translation of several key proteins regulating the cell cycle. These effects lead to a cell cycle block at the G1 phase. In animal models of human cancers, temsirolimus inhibited the growth of a diverse range of cancer types even when an intermittent dosing schedule was used. The compound also appears to have potential for the blockade of inflammatory responses associated with autoimmune and rheumatic diseases by inhibiting T-cell proliferation. On 11 March 2002, American Home Products changed its name and the name of its subsidiary Wyeth-Ayerst to Wyeth. During the first half of 2004, Wyeth initiated ongoing recruitment into a US phase III trial comparing orally administered temsirolimus plus letrozole versus letrozole alone as first-line treatment among approximately 1200 postmenopausal women with advanced breast cancer. The multicentre, randomised, double-blind, placebo-controlled trial is estimated to last 34 months. All subjects will have the option of participating in the long-term follow-up phase of the trial that involves follow-up every 3 months until disease progression; the primary endpoint is overall progression-free survival. In August 2004, the US FDA granted temsirolimus fast-track status for the first-line treatment of poor-prognosis patients with advanced renal cell carcinoma. Previously in March 2002, temsirolimus received fast-track status from the FDA for the treatment of renal cell carcinoma in patients who failed to respond to interleukin-2 treatment. Wyeth intends to file a NDA for temsirolimus for this indication by 2006. Researchers from Wyeth presented the findings from a preclinical study of temsirolimus at the 67th Annual Scientific Meeting of the American College of Rheumatology and the 38th Annual Meeting Association of Rheumatology Health Professionals (ACR/ARHP-2003) [Orlando, FL, USA; October 2003]. The aim of this study was to determine the effect of temsirolimus on lymphocyte proliferation and cytokine production. Since lymphocytes and cytokines are significantly involved in the pathogenesis of rheumatoid arthritis, tems

Topics: Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; Humans; Immunosuppressive Agents; Neoplasms; Rheumatic Diseases; Sirolimus

Targeted molecular therapeutics are tailored toward the genetic abnormalities that cause tumor progression. Modulation of certain signaling pathways that are aberrant in cancer cells has the potential to provide an effective, nontoxic approach to therapy in a broad range of cancers. Agents targeting BCR-ABL (imatinib mesylate [formerly known as STI-571], Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ), retinoid receptor fusion proteins (all-trans retinoic acid), ErbB-2 or HER2/neu (trastuzumab, Herceptin; Genentech, Inc, South San Francisco, CA), epidermal growth factor receptor (IMC-C225 and ZD1839), and the phosphatidylinositol 3-kinase pathway (CCI-779) have all induced remarkable, nontoxic responses in a subset of patients with cancer and abnormalities in the corresponding signal transduction cascades. To achieve successful individualized therapy, the specific components within the aberrant signaling pathways that are driving the pathophysiology of the tumors must be identified in each patient. Molecular diagnostics can identify patients in whom the target is aberrant; linking molecular diagnostics with effective molecular therapeutics will be necessary to translate these concepts into approaches that will alter the outcome for patients with cancer. In addition, intermediary markers and/or molecular imaging techniques must be used to identify the biologically relevant dose that is sufficient to inhibit the target of interest. This review focuses on the P13K pathway, and novel molecules targeting this pathway, to illustrate the questions and challenges underlying the implementation of molecular therapeutics in breast and ovarian cancer.

Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

Topics: Animals; Antibiotics, Antineoplastic; Biological Transport; Clinical Trials as Topic; Humans; Immunophilins; Models, Biological; Models, Genetic; Protein Folding; Protein Isoforms; Protein Kinases; Protein Structure, Tertiary; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The treatment of patients with metastatic soft tissue sarcomas (STS) is complex. There are limited agents available and many are associated with significant toxicity. When evaluating a patient with metastatic disease, physicians should ask themselves whether there is a role for surgery to render the patient free of disease. Combination chemotherapy in patients who have not received chemotherapy in the adjuvant setting is one option, particularly in a young patient with a good performance status. Sequential single-agent therapy for patients who are more elderly or debilitated by their disease may be more appropriate. Gemcitabine appears to be an agent with activity, particularly in patients with leiomyosarcomas. The data regarding prolonged gemcitabine infusions suggest improved activity that was predicted based on prolonged intracellular gemcitabine levels. Because of these data, the prolonged infusion schedule should be used. In addition, because of the paucity of effective agents, consideration of clinical trial participation for patients with newly diagnosed metastatic disease is appropriate, particularly in chemotherapy-insensitive histologies. The role of the newer agents (eg, ecteinascidin-743, epothilones, and mammalian target of rapamycin) is undefined. Ecteinascidin-743 has been the most extensively tested agent, and its ability to slow growth kinetics of a tumor and stabilize it clinically is intriguing. Data regarding the response to BMS-247550 will be published shortly and will help define the further role of epothilones in this disease. There is a preclinical rationale that makes the mammalian target of rapamycin inhibitors attractive for the treatment of muscle-derived neoplasms. In addition, there are cell-line data suggesting activity in rhabdomyosarcoma. These agents are being tested in adult STS and will likely be tested in pediatric histologies when there are more safety data available in that population. SU11248 will continue to be tested in patients refractory to imatinib mesylate and may well prove to be another active agent for patients with gastrointestinal stromal tumors. As depicted by the analysis of gemcitabine efficacy, agents with activity in a subgroup of STS may be overlooked by the "come one come all" approach to clinical trials in STS. Identifying key targets in specific STS will be helpful in the testing of newer molecularly targeted agents. Biologic differences will support histology-specific trials to better understand

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Dioxoles; Docetaxel; Epothilones; Guanidines; Humans; Indoles; Isoquinolines; Protein Kinase Inhibitors; Protein Kinases; Pyrazines; Pyrroles; Sarcoma; Sirolimus; Sunitinib; Taxoids; Tetrahydroisoquinolines; TOR Serine-Threonine Kinases; Trabectedin

Wyeth Research (formerly Wyeth-Ayerst Research) is developing the sirolimus (rapamycin) analog CCI-779 as a potential treatment for various cancers [320924]. By November 2001, phase III trials had been initiated [428972], [429576]. In October 2001, Raymond James predicted filing in 2003, with a potential launch in 2005 [426718]. In March 2002, CCI-779, was designated for fast-track development by the FDA for the treatment of renal cell carcinoma after failure of initial therapy [442535]; at this time phase III trials for renal cell carcinoma and phase II trials for various solid tumors were ongoing [444030]. In March 2002, Wyeth revealed that filing was anticipated for 2004/2005 [443491]. In June and August 2001, Lehman Brothers predicted sales of US $40 million ($20 million in the US) in 2003, rising to US $75 million ($38 million in the US) in 2004 [418901], [420809]. In October 2001, analysts at Raymond James expected potential sales of the product at US $250 million [426718]. In May 2002, a patent (WO-00240000) was published claiming CCI-779 to be useful for the treatment of cancers of various origins, including renal, breast, cervical, uterine, head and neck, lung, prostate, pancreatic, ovarian, colon, lymphoma and melanoma.

Topics: Animals; Antibiotics, Antineoplastic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Contraindications; Humans; Neoplasms; Protein Synthesis Inhibitors; Sirolimus

Rapamycin and CCI-779 have significant in vitro and in vivo anti-proliferative activity against a broad range of human tumor cell lines, justifying the clinical evaluation of this class of agent in cancer patients. Preliminary results from phase I studies of CCI-779 suggest that the agent is well tolerated and has anti-tumor activity. The challenge to investigators is to efficiently determine what role this class of agent will play in the treatment of cancer patients.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Carrier Proteins; Cell Cycle Proteins; Cell Division; Clinical Trials as Topic; Cyclic AMP-Dependent Protein Kinases; Drug Design; Enzyme Inhibitors; Eukaryotic Initiation Factors; Everolimus; Humans; Immunosuppressive Agents; Mice; Neoplasm Proteins; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Protein Processing, Post-Translational; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Rapamycin and its derivatives, CCI-779 and RAD-001, inhibit the mammalian target of rapamycin (mTOR), downregulating translation of specific mRNAs required for cell cycle progression from G1 to S phase. Preclinically, mTOR inhibitors potently suppress growth and proliferation of numerous tumor cell lines in culture or when grown in mice as xenografts. CCI-779 and RAD-001 are being developed as antitumor drugs and are undergoing clinical trials. Clinically, CCI-779 has shown evidence of antitumor activity but induced relatively mild side effects in patients. Here we discuss potential antitumor mechanisms and resistance mechanisms of mTOR inhibitors, and summarize the current status of these compounds as novel antitumor agents.

Topics: Antineoplastic Agents; Cell Division; Clinical Trials, Phase I as Topic; Drug Resistance, Neoplasm; Everolimus; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Cells, Cultured

Over the last 20 years, progress in the therapy of small cell lung cancer has been painfully slow. Despite dramatic initial responses to chemotherapy, most patients relapse quickly with an overall 5-year survival of about 5%. Recent trials however offer some hope at changing this picture. Combining standard regimens with newer agents has doubled median survival in some cases. The use of novel targeted agents holds the promise of significantly increasing the survival in this disease, with manageable toxicity. This review outlines current treatment strategies, summarizes recent clinical trials and offers a view of what the next 5 years may hold for the treatment of small cell lung cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged-Ring Compounds; Carcinoma, Small Cell; Clinical Trials as Topic; Humans; Lung Neoplasms; Palliative Care; Phosphoinositide-3 Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Sirolimus; Taxoids; Topoisomerase I Inhibitors

The high frequency of mutations in cancer cells which result in altered cell cycle regulation and growth signal transduction, conferring a proliferative advantage, indicates that many of these aberrant mechanisms may be strategic targets for cancer therapy. The macrolide fungicide rapamycin, a natural product with potent antimicrobial, immunosuppressant, and anti-tumor properties, inhibits the translation of key mRNAs of proteins required for cell cycle progression from G1 to S phase. Rapamycin binds intracellularly to the immunophilin FK506 binding protein 12 (FKBP12), and the resultant complex inhibits the protein kinase activity of a protein kinase termed mammalian target of rapamycin (mTOR). The inhibition of mTOR, in turn, blocks signals to two separate downstream pathways which control the translation of specific mRNAs required for cell cycle traverse from G1 to S phase. Blocking mTOR affects the activity of the 40S ribosomal protein S6 kinase (p70s6k) and the function of the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), leading to growth arrest in the the G1 phase of the cell cycle. In addition to its actions on p70s6k and 4E-BP1, rapamycin prevents cyclin-dependent kinase activation, inhibits retinoblastoma protein (pRb) phosphorylation, and accelerates the turnover of cyclin D1 that leads to a deficiency of active cdk4/cyclin D1 complexes, all of which can inhibit cell cycle traverse at the G1/S phase transition. Both rapamycin and CCI-779, an ester analog of rapamycin with improved pharmaceutical properties and aqueous solubility, have demonstrated impressive activity against a broad range of human cancers growing in tissue culture and in human tumor xenograft models, which has supported the development of compounds targeting rapamycin-sensitive signal-transduction pathways. CCI-779 has completed several phase I clinical evaluations and is currently undergoing broad disease-directed efficacy studies. The agent appears to be well tolerated at doses that have resulted in impressive anti-tumor activity in several types of refractory neoplasms. Important challenges during clinical development include the definition of a recommended dose range associated with optimal biological activity and maximal therapeutic indices, as well as the ability to predict which tumors will be sensitive or resistant to CCI-779.

Topics: Adaptor Proteins, Signal Transducing; Antibiotics, Antineoplastic; Carrier Proteins; Cell Cycle Proteins; Clinical Trials, Phase I as Topic; Humans; Phosphoproteins; Protein Kinase Inhibitors; Protein Kinases; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Tacrolimus Binding Protein 1A; TOR Serine-Threonine Kinases

Rapamycin (sirolimus) is a macrolide, related to cyclosporine with immunosuppressive properties and antiproliferative activity in various human tumor cells lines and tumor xenograft models. The cytosolic kinase mTOR which controls the initiation of the translation of messenger RNA is the main known target of rapamycin. During clinical studies, rapamycin given by oral route as immunosuppressant did not show dose-limited toxicity and only asymptomatic thrombopenia and hyperlipemia were observed. In murine models, best antitumoral activity was observed using parental routes. CCI-779, an analog formulated for intravenous use has antitumor activity without significant immunosuppressive property in mice and is currently in phase I trials in man.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Clinical Trials, Phase I as Topic; Disease Models, Animal; Humans; Immunosuppressive Agents; Injections, Intravenous; Mice; Neoplasm Transplantation; Protein Biosynthesis; Protein Kinase Inhibitors; RNA, Messenger; Sirolimus; Transplantation, Heterologous; Tumor Cells, Cultured

Sunitinib is a multi-target tyrosine kinase inhibitor (TKI) that inhibits VEGF receptor 1, 2, 3 (VEGFRs), platelet-derived growth factor receptor (PDGFR), colony-stimulating factor receptor (CSFR), and the stem cell factor receptor c-KIT. Temsirolimus inhibits mammalian target of rapamycin (mTOR) through binding to intracellular protein FKBP-12. Both agents are approved for the treatment of metastatic renal cell carcinoma (mRCC), have different anticancer mechanisms, and non-overlapping toxicities. These attributes form the scientific rationale for sequential combination of these agents. The primary objective of the study was to investigate the efficacy of alternating sunitinib and temsirolimus therapy on progression-free survival (PFS) in mRCC.. We undertook a phase II, multi-center, single cohort, open-label study in patients with mRCC. Patients were treated with alternating dosing of 4 weeks of sunitinib 50 mg PO daily, followed by 2 weeks rest, then 4 weeks of temsirolimus 25 mg IV weekly, followed by 2 weeks rest (12 weeks total per cycle). The primary endpoint was PFS. Secondary endpoints included clinical response rate and characterization of the toxicity profile of this combination therapy.. Nineteen patients were enrolled into the study. The median observed PFS (n = 13 evaluable for PFS) was 8.8 months (95% CI 6.8-25.2 months). Best responses achieved were five partial response, nine stable disease, and three disease progression according to RECIST 1.1 guidelines (two non-evaluable). The most commonly observed toxicities were fatigue, platelet count decrease, creatinine increased, diarrhea, oral mucositis, edema, anemia, rash, hypophosphatemia, dysgeusia, and palmar-plantar erythrodysesthesia syndrome.. Alternating sunitinib and temsirolimus did not improve the PFS in patients with mRCC.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Kidney Neoplasms; Pyrroles; Sirolimus; Sunitinib

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.

Topics: Adolescent; Alanine Transaminase; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Etoposide; Humans; MTOR Inhibitors; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphoproteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sirolimus; TOR Serine-Threonine Kinases

Temsirolimus, a mTOR inhibitor, and AZD2171, a VEGFR inhibitor, have independently shown activity in patients with gynecological malignancies. Understanding the pivotal role of the PI3K/PTEN/AKT/mTOR pathway in regulating angiogenesis, a phase I study utilizing Temsirolimus and AZD2171 was initiated to study the safety of targeting the mTOR and VEGF pathway in patients with recurrent or refractory gynecological malignancies.. Patients with advanced gynecological cancers were enrolled in this phase 1 study with Temsirolimus and AZD2171. A traditional 3 + 3 design was followed. The primary objective was to determine the MTD of the combination. Secondary objectives included efficacy, progression free survival (PFS) and toxicity profile. An expansion phase was planned after the MTD was determined.. The study enrolled 11 patients over 16 months. All patients were enrolled in dose level 1. Due to toxicity, the trial was halted at dose level 1. No MTD was determined. The most common grade 3/4 toxicities included hypertension, thrombocytopenia, thromboembolic events, and hypertriglyceridemia. Five patients were evaluable for best overall clinical response. The best overall clinical response was stable disease. Two patients died without documented progression of disease. The median PFS was 7.2 months.. Despite a conservative dose escalation, the toxicity data demonstrated that the combination of AZD2171 and Temsirolimus was not tolerable. Increased awareness of novel toxicities, pharmacological interactions, coupled with strict patient selection and early mitigation of side effects may enhance phase I clinical trial development.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Genital Neoplasms, Female; Humans; Quinazolines; Sirolimus; TOR Serine-Threonine Kinases

The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with. From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and. In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Mutation; Sirolimus; Tumor Suppressor Protein p53

Mantle cell lymphoma (MCL) is a rare, incurable lymphoma subtype characterized by heterogeneous outcomes. To better understand the clinical behavior and response to treatment, predictive biomarkers are needed. Using residual archived material from patients enrolled in the MCL3001 (RAY) study, we performed detailed analyses of gene expression and targeted genetic sequencing. This phase III clinical trial randomized patients with relapsed or refractory MCL to treatment with either ibrutinib or temsirolimus. We confirmed the prognostic capability of the gene expression proliferation assay MCL35 in this cohort treated with novel agents; it outperformed the simplified MCL International Prognostic Index in discriminating patients with different outcomes. Regardless of treatment arm, our data demonstrated that this assay captures the risk conferred by known biological factors, including increased MYC expression, blastoid morphology, aberrations of TP53, and truncated CCND1 3' untranslated region. We showed the negative impact of BIRC3 mutations/deletions on outcomes in this cohort and identified that deletion of chromosome 8p23.3 also negatively impacts survival. Restricted to patients with deletions/alterations in TP53, ibrutinib appeared to abrogate the deleterious impact on outcome. These data illustrate the potential to perform a molecular analysis of predictive biomarkers on routine patient samples that can meaningfully inform clinical practice.

Topics: 3' Untranslated Regions; Adenine; Adult; Biological Factors; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Sirolimus

The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of four (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of six prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic adverse events (AE) were common. Three grade 5 AE occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL (clinicaltrials gov. Identifier: NCT01076543).

Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lenalidomide; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Autologous; Treatment Outcome

Resistance to treatment with inhibitors of mammalian target of rapamycin (mTOR) is partially mediated by activation of epidermal growth factor receptor (EGFR). We conducted a phase I study to determine the recommended phase II dose (RP2D) and dose-limiting toxicities (DLT) of temsirolimus (mTOR inhibitor) combined with erlotinib (EGFR inhibitor) in patients with refractory solid tumors.. Standard "3 + 3" design was used for dose escalation. An expansion cohort at RP2D included only patients with squamous histology or mutations relevant to PI3K or EGFR pathway activation. Patients started daily erlotinib 7 days prior to starting temsirolimus on cycle 1. Intravenous temsirolimus was then administered weekly. Starting dose levels were 15 mg for temsirolimus and 100 mg for erlotinib.. Forty-four patients received treatment on this study (28 in dose escalation and 16 in the expansion cohort). The RP2D was temsirolimus 25 mg IV weekly and erlotinib 100 mg orally daily. Two patients experienced DLTs (G3 dehydration and G4 renal failure). The most common drug-related adverse events (all grades) were rash, mucositis/stomatitis, diarrhea, nausea and fatigue. No complete or partial responses were observed. The median duration on this study was 69 days (range 3-770) for escalation and 88 days (range 25-243) for expansion cohorts. Among 11 response-evaluable patients in the expansion cohort, 9 (82%) had stable disease and 2 (18%) had progressive disease.. The combination of temsirolimus and erlotinib at the RP2D was well tolerated, and the regimen resulted in prolonged disease stabilization in selected patients (NCT00770263).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Disease Progression; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Male; Middle Aged; Mutation; Neoplasms; Phosphatidylinositol 3-Kinase; Sirolimus; Treatment Outcome

The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors.. Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target.. Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2).. Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Female; Gastrointestinal Neoplasms; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Sirolimus; Treatment Outcome

Despite frequent PTEN (phosphatase and tensin homologue) loss and Akt/mammalian target of rapamycin (mTOR) signaling in prostate cancer, the disease is insensitive to single-agent mTOR inhibition. Insulin-like growth factor-1 receptor inhibition might mitigate the feedback inhibition by Torc1 inhibitors, suppressing downstream Akt activation and, thus, potentiating the antitumor activity of mTOR inhibition.. In the present phase I study, patients with metastatic castration-resistant prostate cancer received 6 mg/kg cixutumumab and 25 mg temsirolimus intravenously each week. The primary objective was safety and tolerability. Temsirolimus was decreased if ≥ 2 dose-limiting toxicities (DLTs) were observed in 6 patients. The correlative analyses included measurement of circulating tumor cells, [18F]-fluoro-2-deoxyglucose positron emission tomography, 16β-[18F]-fluoro-α-dihydrotestosterone positron emission tomography, and tumor biopsy.. A total of 16 patients were enrolled across 3 cohorts (1, -1, -2). Two DLTs (grade 3 oral mucositis) were observed in cohort 1 (temsirolimus, 25 mg), and 1 DLT (grade 3 lipase) in cohort -1 (temsirolimus, 20 mg). The most common adverse events included hyperglycemia (100%; 31% grade 3), oral mucositis (63%; 19% grade 3), and diarrhea (44%; 0 grade 3). Low-grade pneumonitis occurred in 7 of 11 patients (44%; 0 grade 3), prompting the opening of a 3-weekly cohort (temsirolimus, 20 mg/kg), without pneumonitis events. No patient had a >50% decline in prostate-specific antigen from baseline. The best radiographic response was stable disease, with median study duration of 22 weeks (range, 7-63 weeks).. Despite a strong scientific rationale for the combination, temsirolimus plus cixutumumab demonstrated limited antitumor activity and a greater than expected incidence of toxicity, including low-grade pneumonitis and hyperglycemia. Hence, the trial was stopped in favor of alternative androgen receptor/phosphatidylinositol 3-kinase-directed combinatorial therapies.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptor, IGF Type 1; Sirolimus; TOR Serine-Threonine Kinases

Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose.. Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg.. We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1).. Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Drug Therapy, Combination; Female; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Phosphorylcholine; Prospective Studies; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance.. In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m. Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms.. The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Drug Resistance, Neoplasm; ErbB Receptors; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Progression-Free Survival; Protein Kinase Inhibitors; Sirolimus; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases

Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined.. In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others.. The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65-4.18) in favor of SUN. There was no trend for overall survival.. Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; International Agencies; Kidney Neoplasms; Male; Middle Aged; Sirolimus; Societies, Medical; Sunitinib; Survival Rate; Treatment Outcome; Young Adult

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Humans; Immunotherapy; Lymphoma, Mantle-Cell; Male; Middle Aged; Prednisone; Rituximab; Sirolimus; Survival Rate; Thrombocytopenia; Vincristine

Temsirolimus has level 1 evidence for initial treatment of poor-risk patients with advanced renal cell carcinoma (mRCC), but its efficacy has not been directly compared with an antiangiogenic tyrosine kinase inhibitor (vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKi]) in this setting.. To evaluate temsirolimus versus pazopanib as first-line therapy in patients with mRCC, predominant clear-cell features, and clinical characteristics of a poor prognosis.. A randomized (1:1) phase II trial in 69 treatment-naïve mRCC patients and with three or more predictors of short survival for temsirolimus was conducted during 2012-2017 in a single academic cancer center. Crossover to the alternative treatment upon discontinuation of the first-line agent was permitted.. Mechanistic target of rapamycin inhibitor temsirolimus and VEGFR TKi pazopanib.. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), safety, and patient-reported outcomes (PROs). Radiographic response was assessed by blinded radiologists. Efficacy outcomes were adjusted by prior nephrectomy status, prior interleukin-2 treatment, and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score.. Thirty-five patients received temsirolimus and 34 received pazopanib upfront; 72% overall had poor risk by IMDC. Median PFS in the first line was 2.7mo with temsirolimus and 5.2mo with pazopanib (adjusted hazard ratio [HR] 1.36, 95% confidence interval [CI] 0.84-2.22; p=0.210). Median OS was 7.1mo with temsirolimus and 11.9mo with pazopanib (adjusted HR 1.16, 95% CI 0.70-1.93; p=0.558), and ORRs were 5.9% and 21.2%, respectively (adjusted odds ratio 5.2, 95% CI 0.9-29.3; p=0.062). PRO measures favored pazopanib. Five patients discontinued first-line therapy due to adverse events.. Temsirolimus and pazopanib had modest activity in patients with poor-risk clear-cell mRCC, and therefore their use should be discouraged in this setting.. We evaluated outcomes of advanced renal cell carcinoma patients presenting with aggressive features when treated with temsirolimus or pazopanib as first-line therapy. Survival was <1yr for most, suggesting that more efficacious alternative treatments should be favored for these patients.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Pyrimidines; Risk Assessment; Single-Blind Method; Sirolimus; Sulfonamides

The primary aim of this clinical trial was to prioritize bevacizumab or temsirolimus for additional investigation in rhabdomyosarcoma (RMS) when administered in combination with cytotoxic chemotherapy to patients with RMS in first relapse with unfavorable prognosis.. Patients were randomly assigned to receive bevacizumab on day 1 or temsirolimus on days 1, 8, and 15 of each 21-day treatment cycle, together with vinorelbine on days 1 and 8, and cyclophosphamide on day 1 for a maximum of 12 cycles. Local tumor control with surgery and/or radiation therapy was permitted after 6 weeks of treatment. The primary end point was event-free survival (EFS). Radiographic response was assessed at 6 weeks. The study had a phase II selection that was design to detect a 15% difference between the two regimens (α = .2; 1-β = 0.8; two sided test).. Eighty-seven of 100 planned patients were enrolled when the trial was closed after the second interim analysis after 46 events occurred in 68 patients with sufficient follow-up. The O'Brien Fleming boundary at this analysis corresponded to a two-sided. Patients who received temsirolimus had a superior EFS compared with bevacizumab. Temsirolimus has been selected for additional investigation in newly diagnosed patients with intermediate-risk RMS.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Child; Cyclophosphamide; Disease Progression; Feasibility Studies; Female; Humans; Male; Neoplasm Recurrence, Local; Progression-Free Survival; Rhabdomyosarcoma; Sirolimus; Time Factors; United States; Vinorelbine; Young Adult

Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment.. A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied.. 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8-65.7], median time to progression 6.8 months (95% CI 5.5-9.2) and median overall survival (OS) 18.2 months (95% CI 12.9-27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3-5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS.. In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations.. ClinicalTrials.gov: NCT01264341.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53-82), with pre-treatment PSA of 205.3 (11.1-1801.0), previously treated with a median of 2 (0-5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n = 4) or 25 mg (n = 17) with bevacizumab 10 mg/kg every 2 weeks (n = 21). Median time to progression was 2.6 months (95% CI, 1.2-3.9) and the median best PSA change from baseline to 12 weeks was a 32% increase (-40-632%) which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had ≥ grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In exploratory analysis, a decrease in CTC levels was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. Conclusions The combination of temsirolimus and bevacizumab showed limited clinical activity in mCRPC patients previously treated with chemotherapy and was associated with significant adverse events (AEs). Transient decrease in CTC levels was independent from PSA response. NCT01083368.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepines; Bevacizumab; Biomarkers, Tumor; Disease Progression; Drug Resistance, Neoplasm; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Prostatic Neoplasms, Castration-Resistant; Pyrroles; Salvage Therapy; Sirolimus; Tissue Distribution; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Temsirolimus 175 mg once-weekly for 3 weeks, followed by 75 mg once-weekly intravenously dosed (175/75 mg) is approved in the European Union for treatment of relapsed/refractory mantle cell lymphoma (MCL). A phase IV study explored whether similar efficacy, but improved safety could be achieved with 75 mg without 175 mg loading doses (ClinicaTrials.gov: NCT01180049). Patients with relapsed/refractory MCL were randomized to once-weekly temsirolimus 175/75 mg (n = 47) or 75 mg (n = 42). Treatment continued until objective disease progression. Primary endpoint: progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). Median PFS was 4.3 versus 4.5 months (hazard ratio [HR] 0.731; 80% confidence interval [CI], 0.520-1.027), and median OS 18.7 versus 11.0 months (HR 0.681; 80% CI, 0.472-0.982) with 175/75 mg versus 75 mg. There were fewer patients with serious AEs, dose reduction, or death with 175/75 mg (57.4%, 48.9%, and 48.9%) versus 75 mg (73.8%, 64.3%, and 65.1%). Temsirolimus 175/75 mg remains the preferred dosing regimen for relapsed/refractory MCL.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Injections, Intravenous; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Salvage Therapy; Sirolimus; Survival Rate

Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal tumor that typically presents with multiple abdominal masses. Initial treatment is multimodal in nature. Patients with relapsed DSRCT have a poor prognosis, and there are no standard therapies. We report our experience with five patients treated with vinorelbine, cyclophosphamide, and temsirolimus (VCT). Median number of VCT courses delivered was 7 (range 4-14 courses), and partial response was observed in all patients. Median time to progression or relapse was 8.5 months (range 7-16 months). Neutropenia and mucositis were most common toxicities (n = 4 each).

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Desmoplastic Small Round Cell Tumor; Female; Humans; Male; Mucositis; Neoplasm Recurrence, Local; Neutropenia; Sirolimus; Vinblastine; Vinorelbine

Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma.. Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi.. The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients.. The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Sirolimus; Sorafenib; Survival Rate

Bladder cancer is the 7th cause of death from cancer in men and 10th in women. Metastatic patients have a poor prognosis with a median overall survival of 14 months. Until recently, vinflunine was the only second-line chemotherapy available for patients who relapse. Deregulation of the PI3K/AKT/mTOR pathway was observed in more than 40% of bladder tumors and suggested the use of mTOR as a target for the treatment of urothelial cancers.. This trial assessed the efficacy of temsirolimus in a homogenous cohort of patients with recurrent or metastatic bladder cancer following first-line chemotherapy. Efficacy was measured in terms of non-progression at two months according to the RECIST v1.1 criteria. Based on a two-stage optimal Simon's design, 15 non-progressions out of 51 evaluable patients were required to claim efficacy. Patients were treated at a weekly dose of 25 mg IV until progression, unacceptable toxicities or withdrawal.. Among the 54 patients enrolled in the study between November 2009 and July 2014, 45 were assessable for the primary efficacy endpoint. A total of 22 (48.9%) non-progressions were observed at 2 months with 3 partial responses and 19 stable diseases. Remarkably, 4 patients were treated for more than 30 weeks. Fifty patients experienced at least a related grade1/2 (94%) and twenty-eight patients (52.8%) a related grade 3/4 adverse event. Eleven patients had to stop treatment for toxicity. This led to recruitment being halted by an independent data monitoring committee with regard to the risk-benefit balance and the fact that the primary objective was already met.. While the positivity of this trial indicates a potential benefit of temsirolimus for a subset of bladder cancer patients who are refractory to first line platinum-based chemotherapy, the risk of adverse events associated with the use of this mTOR inhibitor would need to be considered when such an option is envisaged in this frail population of patients. It also remains to identify patients who will benefit the most from this targeted therapy.. ClinicalTrials.gov Identifier: NCT01827943 (trial registration date: October 29, 2012); Retrospectively registered.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Retreatment; Sirolimus; Treatment Outcome; Urinary Bladder Neoplasms

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Humans; International Agencies; Lymphoma, Mantle-Cell; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Salvage Therapy; Sirolimus; Survival Rate

Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy.. In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety.. Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55-0.91), 0.99 (0.78-1.26), and 0.97 (0.77-1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified.. PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Endometrial Neoplasms; Epothilones; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Sirolimus

Multiple studies have demonstrated the efficacy and safety of ibrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). This first-in-class inhibitor of Bruton's tyrosine kinase has become a standard treatment for patients with CLL and MCL.. We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with ibrutinib versus comparators. Data were pooled from 4 completed randomized controlled studies that had included 756 ibrutinib-treated and 749 comparator-treated patients with CLL/SLL or relapsed/refractory MCL. Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates.. The median treatment duration was 13.3 months (maximum, 28.2 months) for ibrutinib and 5.8 months (maximum, 27.3 months) for comparators. When adjusted for exposure, diarrhea, atrial fibrillation, and hypertension were the only common grade ≥ 3 AEs more often reported with ibrutinib than with the comparators. Dose reductions (7% vs. 14%) and discontinuation (12% vs. 16%) because of AEs occurred less often with ibrutinib, and deaths due to AEs occurred at similar rates (6% vs. 7%). When adjusted for exposure, the corresponding data were all lower with ibrutinib than with the comparators (0.06 vs. 0.22, 0.11 vs. 0.22, and 0.06 vs. 0.09 patient-exposure-years, respectively). The prevalence of common grade 3/4 AEs with ibrutinib generally decreased over time, with the exception of hypertension.. These results from an integrated analysis support a favorable benefit/risk profile of ibrutinib in patients with CLL/SLL and MCL.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Patient Safety; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Rituximab; Sirolimus; Survival Rate

Background Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors. Methods Two-part study: dose escalation, to determine the maximum tolerated dose (MTD) of selumetinib in combination with erlotinib 100 mg once daily (QD) or temsirolimus 25 mg once weekly, followed by dose expansion at the respective combination MTDs to further investigate safety and anti-tumor effects. Results 48 patients received selumetinib plus erlotinib and 32 patients received selumetinib plus temsirolimus. The MTD with erlotinib 100 mg QD was selumetinib 100 mg QD, with diarrhea being dose limiting. The most common all grade adverse events (AEs): diarrhea, rash, nausea, and fatigue. Four (8.3%) patients had ≥12 weeks stable disease. The MTD with temsirolimus 25 mg once weekly was selumetinib 50 mg twice daily (BID), with mucositis and neutropenia being dose limiting. The most commonly reported AEs: nausea, fatigue, diarrhea, and mucositis. Ten (31.3%) patients had ≥12 weeks stable disease. The combination PK profiles were comparable to previously observed monotherapy profiles. Conclusions MTDs were established for selumetinib in combination with erlotinib or temsirolimus. Overlapping toxicities prevented the escalation of selumetinib to its recommended phase II monotherapy dose of 75 mg BID.. ClinicalTrials.gov NCT00600496; registered 8 July 2009.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Dose-Response Relationship, Drug; Erlotinib Hydrochloride; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Sirolimus

Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Pyrazoles; Pyrimidines; Quality of Life; Retreatment; Sirolimus; Treatment Outcome

Preclinical studies suggest synergistic antitumour effects of mammalian target of rapamycin (mTOR) inhibitor such as temsirolimus combined with anti-EGFR monoclonal antibody such as cetuximab.. Combination of T + C showed significant but manageable toxicities. Due to modest clinical activity, further evaluation is not recommended. Molecular selection could potentially increase the objective response rate and should be implemented during drug development.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neoplasms; Sirolimus; Survival Analysis

Patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited treatment options. Sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results.. In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate.. The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis.. Sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. © 2017 American Cancer Society.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Mutation; Niacinamide; Phenylurea Compounds; Proto-Oncogene Proteins B-raf; Radiation Tolerance; Sirolimus; Sorafenib; Thyroid Neoplasms; Treatment Outcome

Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carcinoma (ccRCC) with a median time to progression shorter than 1 year. The objective is to discover predictive markers of response to adapt the treatment at diagnosis.. Prospective phase 2 multi-centre trials were conducted in ccRCC patients initiating sunitinib (54 patients) or bevacizumab (45 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). The plasmatic level of CXCL7 at baseline was correlated with progression-free survival (PFS).. The cut-off value of CXCL7 for PFS was 250 ng ml. CXCL7 may be considered as a predictive marker of sunitinib efficacy for ccRCC patients.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; beta-Thromboglobulin; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indoles; Kidney Neoplasms; Killer Cells, Natural; Lymphocytes, Tumor-Infiltrating; Macrophages; Male; Mice; Middle Aged; Neoplasm Grading; Neoplasm Transplantation; Nephrectomy; Neutrophils; Prospective Studies; Pyrroles; Retrospective Studies; Sirolimus; Sunitinib; Survival Rate

Activating events along the PI3K/mTOR pathway are common in head and neck squamous cell carcinomas (HNSCC), and preclinical studies suggest additive or synergistic effects when combining mTORC1 inhibitors with carboplatin and paclitaxel chemotherapy.. In this single-institution phase II study, the combination of temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m2 administered on days 1 and 8 of a 21-day cycle was evaluated in 36 patients with recurrent and/or metastatic (R/M) HNSCC. The primary end point was objective response rate after two cycles of treatment. Secondary end points include the safety and tolerability profile and overall survival. Correlative studies with exome mutational analysis were performed in pre-treatment biopsy samples from 21 patients.. Fifteen (41.7%) patients had an objective response, which were all partial responses, and 19 (52.3%) patients had stable disease as best response. The two patients who were designated as 'non-responders' were removed from study prior to two cycles of treatment, but are included in the efficacy and safety analyses. The median duration on study was 5.3 months and the median progression-free survival and overall survival were 5.9 months (95% confidence interval, 4.8-7.1) and 12.8 months (95% confidence interval, 9.8-15.8), respectively. The most common grade 3 and 4 adverse events were hematologic toxicities. Three (3.8%) patients developed neutropenic fever on study. Three of four patients with PIK3CA mutations experienced tumor regressions, and responses were also seen in patients with other genetic alterations in the PI3K/mTOR pathway.. The combination of temsirolimus with low-dose weekly carboplatin and paclitaxel appears to have meaningful clinical efficacy in the treatment of R/M HNSCC. This regimen has a relatively high response rate compared to other treatments evaluated in R/M HNSCC, and potential associations with genetic alterations in the PI3K/mTOR pathway should be further explored.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Sirolimus; Squamous Cell Carcinoma of Head and Neck

Triple-negative breast cancer (TNBC) classified by transcriptional profiling as the mesenchymal subtype frequently harbors aberrations in the phosphoinositide 3-kinase (PI3K) pathway, raising the possibility of targeting this pathway to enhance chemotherapy response. Up to 30% of mesenchymal TNBC can be classified histologically as metaplastic breast cancer, a chemorefractory group of tumors with a mixture of epithelial and mesenchymal components identifiable by light microscopy. While assays to identify mesenchymal TNBC are under development, metaplastic breast cancer serves as a clinically identifiable surrogate to evaluate potential regimens for mesenchymal TNBC.. To assess safety and efficacy of mammalian target of rapamycin (mTOR) inhibition in combination with liposomal doxorubicin and bevacizumab in patients with advanced metaplastic TNBC.. Phase 1 study with dose escalation and dose expansion at the University of Texas MD Anderson Cancer Center of patients with advanced metaplastic TNBC. Patients were enrolled from April 16, 2009, to November 4, 2014, and followed for outcomes with a cutoff date of November 1, 2015, for data analysis.. Liposomal doxorubicin, bevacizumab, and the mTOR inhibitors temsirolimus or everolimus using 21-day cycles.. Safety and response. When available, archived tissue was evaluated for aberrations in the PI3K pathway.. Fifty-two women with metaplastic TNBC (median age, 58 years; range, 37-79 years) were treated with liposomal doxorubicin, bevacizumab, and temsirolimus (DAT) (N = 39) or liposomal doxorubicin, bevacizumab, and everolimus (DAE) (N = 13). The objective response rate was 21% (complete response = 4 [8%]; partial response = 7 [13%]) and 10 (19%) patients had stable disease for at least 6 months, for a clinical benefit rate of 40%. Tissue was available for testing in 43 patients, and 32 (74%) had a PI3K pathway aberration. Presence of PI3K pathway aberration was associated with a significant improvement in objective response rate (31% vs 0%; P = .04) but not clinical benefit rate (44% vs 45%; P > .99).. Using metaplastic TNBC as a surrogate for mesenchymal TNBC, DAT and DAE had notable activity in mesenchymal TNBC. Objective response was limited to patients with PI3K pathway aberration. A randomized trial should be performed to test DAT and DAE for metaplastic TNBC, as well as nonmetaplastic, mesenchymal TNBC, especially when PI3K pathway aberrations are identified.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Doxorubicin; Elafin; Everolimus; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Polyethylene Glycols; Proportional Hazards Models; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms

Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Pharmacokinetic (PK) characterization of temsirolimus in children is limited and there is no paediatric temsirolimus population PK model available. The objective of this study was to simultaneously characterize the PK of temsirolimus and its metabolite sirolimus in paediatric patients with recurrent solid or central nervous system tumours and to develop a population PK model.. The PK data for temsirolimus and sirolimus were collected as a part of a Children's Oncology Group phase I clinical trial in paediatric patients with recurrent solid tumours. Serial blood concentrations obtained from 19 patients participating in the PK portion of the study were used for the analysis. Population PK analysis was performed by nonlinear mixed effect modelling using NONMEM.. A three-compartment model with zero-order infusion was found to best describe temsirolimus PK. Allometrically scaled body weight was included in the model to account for body size differences. Temsirolimus dose was identified as a significant covariate on clearance. A sirolimus metabolite formation model was developed and integrated with the temsirolimus model. A two-compartment structure model adequately described the sirolimus data.. This study is the first to describe a population PK model of temsirolimus combined with sirolimus formation and disposition in paediatric patients. The developed model will facilitate PK model-based dose individualization of temsirolimus and the design of future clinical studies in children.

Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Models, Biological; Neoplasm Recurrence, Local; Neoplasms; Nonlinear Dynamics; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) were treated with escalating doses of tivantinib (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at the MTD. Separate cohorts were planned for extensive (normal) and poor tivantinib metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results Twenty-nine pts. [median age 58 (range 28-77)] were enrolled (21 in dose escalation and 8 in dose expansion). All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal, ovarian and non-small cell lung. Sixteen out of 21 and 6 out of 8 pts. were evaluable for DLT evaluation per protocol in the dose escalation and dose expansion phases, respectively. Pts remained on study for a median of 71 days (range 18-296). The MTD and RP2D was tivantinib 240 mg twice daily and temsirolimus 20 mg weekly. DLTs included grade (gr) 4 neutropenia (2 pts.; 1 with gr 3 febrile neutropenia), gr 3 abdominal pain (1 pt) and gr 2 mucositis resulting in inadequate drug delivery. The most common treatment related AEs grade ≥ 2 included: anemia (gr 2 in 9 pts., gr 3 in 3 pts), fatigue (gr 2 in 10 pts), anorexia (gr 2 in 9 pts), hypoalbuminemia (gr 2 in 6 pts., gr 3 in 2 pts), hypophosphatemia (gr 2 in 2 pts., gr 3 in 5 pts) and nausea (gr 2 in 6 pts., gr 3 in 1 pt). One pt. with ovarian cancer had a confirmed partial response and remained on study for 10 months, a second patient with ovarian cancer had stable disease and remained on study for 6 months and a third pt. with squamous cell carcinoma of the tongue had stable disease and remained on study for 7 months. Pharmacokinetic analysis showed that there is no interaction in the plasma concentrations between tivantinib and temsirolimus. Conclusions The combination of tivantinib wi

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytochrome P-450 CYP2C19; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrrolidinones; Quinolines; Sirolimus

The current treatment of metastatic renal cell carcinoma (mRCC) revolves around targeted agents, which have resulted in a median overall survival of 22 to 26 months in registration trials. However, the outcomes in a non-trial, real-world Indian population have not yet been evaluated.. The present study was a part of a prospective Clinical Trials Registry-India-registered study, the Kidney Cancer Registry, a prospectively maintained kidney cancer registry. The data of patients with a diagnosis of mRCC from February 2007 to August 2015 who were potential candidates for systemic therapy were extracted from the database and analyzed for treatment patterns and outcomes.. The data from 212 patients were eligible for analysis. Of these 212 patients, 204 (96.2%) received first-line systemic treatment with sunitinib (40.6%), sorafenib (37.7%), pazopanib (2.8%), temsirolimus (2.8%), or everolimus (1.9%). The risk status of 91% of the patients could be stratified using the Heng criteria into favorable (18.9%), intermediate (43.9%), and poor risk (28.3%) categories. The response rate, clinical benefit rate, median progression-free survival, and median overall survival with first-line targeted therapy were 22.5%, 60.7%, 7.09 months, and 12.87 months, respectively. The common adverse events seen included skin rash (31.7%), hypertension (29.4%), grade 3 hand-foot syndrome (27.4%), mucositis (26.4%), dyslipidemia (20%), and hyperglycemia (17.6%). Patients receiving second-line therapy (22.6%) had superior overall survival to patients who had not (16.46 vs. 10.67 months; P = .032).. The present registry-based study is the first, to the best of our knowledge, of its type from India and showed that the overall outcomes in this real-world cohort appear comparable to non-trial data worldwide. An increased incidence of metabolic adverse events that require monitoring during treatment was also found.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indazoles; India; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Practice Patterns, Physicians'; Prospective Studies; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Tertiary Care Centers; Treatment Outcome; Young Adult

Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3 + 3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated. Results Of 33 patients evaluated, all experienced ≥1 treatment-emergent adverse event (TEAE) and 31 had treatment-related TEAEs, most frequently stomatitis and thrombocytopenia. TEAEs were reversible. No deaths were attributed to treatment. Nine patients had dose-limiting toxicities (stomatitis, thrombocytopenia, serum creatinine phosphokinase increase, visual impairment) and the MTD was determined as 45 mg/day pimasertib plus 25 mg/week temsirolimus. However, due to overlapping toxicities no further investigations were performed and the RP2D was not defined. PK profiles of both agents were not adversely affected. Seventeen patients (17/26 patients) had a best response of stable disease; five had stable disease lasting >12 weeks. Conclusions The RP2D was not defined and the pimasertib plus temsirolimus combination investigated did not warrant further study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; MAP Kinase Kinase Kinase 1; MAP Kinase Kinase Kinase 2; Maximum Tolerated Dose; Middle Aged; Neoplasms; Niacinamide; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.. This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74).. Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]).. Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.. Janssen Research & Development, LLC.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Sirolimus; Treatment Outcome

There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity.. Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2.. Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL -1, and 8 at DL -2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2-/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment.. The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia.

Topics: Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Edema; Fatigue; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Recombinant Fusion Proteins; Sirolimus; Treatment Outcome

To evaluate activity and toxicity of mTOR inhibitor temsirolimus in patients with platinum-refractory/resistant ovarian cancer (OC) or advanced/recurrent endometrial carcinoma (EC).. Women with epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. Women with advanced/recurrent EC, no longer amenable to curative surgery and/or radiotherapy were eligible when they had no previous or only adjuvant chemotherapy. Preceding endocrine therapy for metastatic/recurrent disease was allowed. Patients received weekly IV infusions of 25mg temsirolimus. Primary endpoint was progression free survival rate after 4 months (OC) or 6 months (EC). A two stage design was applied.. Forty-four patients (OC: n=22; EC: n=22) were enrolled and received temsirolimus treatment. Median age was 56 years (OC) or 63 years (EC). After eight weeks of treatment, 10 of 21 evaluable patients in the OC cohort and 8 of 20 evaluable patients in the EC cohort had progressive disease. Thus efficacy did not meet the predefined levels during the first stage of recruitment and the trial was stopped. Some patients in both cohorts had long lasting PFS (>7 months). Toxicity of temsirolimus was mild.. Temsirolimus treatment was well tolerated in our patients, but did not meet the predefined efficacy criteria. In our study as in other trials on rapalogs in OC or EC, a few patients had long lasting disease stabilisations.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma; Disease-Free Survival; Drug Resistance, Neoplasm; Early Termination of Clinical Trials; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Platinum Compounds; Response Evaluation Criteria in Solid Tumors; Retreatment; Sirolimus; Young Adult

Pemetrexed is an antifolate chemotherapeutic agent approved for use in non-small cell lung cancer (NSCLC). The mammalian target of rapamycin (mTOR) pathway is implicated in lung cancer development and inhibited by temsirolimus.. We performed a phase I study evaluating the combination of pemetrexed and temsirolimus in advanced non-squamous NSCLC.. Eight patients were enrolled in this study. The dose-limiting toxicities included grade 4 thrombocytopenia, grade 3 leukopenia and grade 3 neutropenia. The maximum tolerated dose was determined to be pemetrexed 375 mg/m2 intravenously on day 1 and temsirolimus 25 mg intravenously on days 1, 8 and 15. No objective responses were noted and 3 patients had stable disease as the best response.. The combination of pemetrexed and temsirolimus is feasible and well tolerated. This combination may be further evaluated in patients with mTOR pathway activation, particularly in those with TSC1 or STK11 mutations.

Topics: Aged; AMP-Activated Protein Kinase Kinases; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Pemetrexed; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins

Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab.. We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus.. The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)).. The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prognosis; Sirolimus; Survival Rate

In this phase II study (NCT00942747), temsirolimus was tested in patients with relapsed or refractory primary CNS lymphoma (PCNSL).. Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once per week. All consecutive patients received 75 mg intravenously once per week.. Thirty-seven eligible patients (median age, 70 years) were included whose median time since their last treatment was 3.9 months (range, 0.1 to 14.6 months). Complete response was seen in five patients (13.5%), complete response unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent Common Toxicity Criteria ≥ 3° adverse event was hyperglycemia in 11 (29.7%) patients, thrombocytopenia in eight (21.6%), infection in seven (19%), anemia in four (10.8%), and rash in three (8.1%). Fourteen blood/CSF pairs were collected in nine patients (10 pairs in five patients in the 25-mg cohort and four pairs in four patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient in the 75-mg cohort; in all others, no drug was found in their CSF.. Single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short lived.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Sirolimus

Mammalian target of rapamycin (mTOR) inhibitors like temsirolimus may result in undesirable AKT upregulation. Metformin inhibits mTOR through different mechanisms and may enhance temsirolimus's antitumor activity. We conducted an open-label phase I dose escalation trial of this drug combination in patients with advanced/refractory cancers.. Temsirolimus, 25 mg weekly, was combined with an escalating daily dose of metformin (level 1: 500; level 2: 1000; level 3: 1500; level 4: 2000 mg) by utilizing a standard 3 + 3 trial design. Treatment was administered in 28-day cycles following initial 2-week metformin titration during the first cycle.. Twenty-one patients (median age, 56 years) with sarcoma (n = 8), colorectal (n = 3), endometrial (n = 4), uterine carcinosarcoma (n = 2), ovarian (n = 2), and other (n = 2) cancers were enrolled. Patients had received median of four prior systemic treatments. Two dose-limiting toxicities were observed (grade 3 mucositis, grade 3 renal failure); both patients continued treatment after dose modification. Fifty-six percent patients had stable disease as best response; clinical benefit rate was 22 %. Patients continued treatment for median of 11 weeks.. Combination temsirolimus/metformin was well tolerated with modestly promising effectiveness among this heavily pretreated patient cohort. We recommend a dose of temsirolimus 25 mg weekly and metformin 2000 mg daily for phase II study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Metformin; Middle Aged; Neoplasms; Response Evaluation Criteria in Solid Tumors; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development.. Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored.. Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR.. Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.

Topics: Class I Phosphatidylinositol 3-Kinases; Endometrial Neoplasms; Female; Humans; Megestrol Acetate; Mutation; Phosphatidylinositol 3-Kinases; Prospective Studies; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Sirolimus; Tamoxifen; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins

Inhibiting VEGF and mammalian target of rapamycin (mTOR) pathways are standard treatment approaches for patients with metastatic renal cell carcinoma (mRCC). Here we report the activity and safety of the VEGF ligand inhibitor bevacizumab and the mTOR inhibitor temsirolimus combination in patients with clear cell (CC) and non-clear cell (NCC) mRCC whose disease had failed to respond to prior VEGF blockade.. In this phase 2 investigator-initiated multicenter study, patients received bevacizumab and temsirolimus. The primary end point was 4-month progression-free survival (PFS) rate. Secondary end points included overall response rate, median overall survival (OS), toxicity, and correlative studies of biomarkers downstream of mTOR.. Forty patients received at least 1 dose of therapy. Thirty-three (82.5%) had favorable/intermediate risk disease according to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 13 (32.5%) with nccRCC histology. Nineteen (48.7%) had primary vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI)-refractory disease. The 4-month PFS rate was 65%. Overall median PFS and OS were 5.6 and 12.2 months. Median PFS and OS were 6.5 and 9.6 months in patients with primary VEGFR TKI-refractory disease, and 5.6 months and 13.1 months in patients with nccRCC. Dose reductions were needed in 80% of patients. Most frequent toxicities included fatigue, hypertension, dyslipidemia, and proteinuria. Dose discontinuation due to adverse events occurred in 27.5% of patients. Baseline tumor immunohistochemistry for phospho-S6 protein was not associated with clinical benefit.. Combining bevacizumab and temsirolimus in patients previously treated with VEGFR TKI was possible but with dose reductions and treatment discontinuations. This combination resulted in modest activity, including in patients with primary VEGF-refractory disease and NCC histology.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.. Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed.. Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2-82.2] in the temozolomide arm and 69.6% (95% CI, 55.8-79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77-1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04-0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus.. Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797-806. ©2016 AACR.

Topics: Adult; Aged; Brain Neoplasms; Chemoradiotherapy; Dacarbazine; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Glioblastoma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Promoter Regions, Genetic; Proportional Hazards Models; Sirolimus; Temozolomide; Tumor Suppressor Proteins; Young Adult

The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower-risk group and 296 days in the higher-risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. We conclude that mTOR-modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.

Topics: Aged; Aged, 80 and over; Blood Cells; Bone Marrow; Bone Marrow Cells; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Sirolimus; Survival Rate; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases; Treatment Outcome

There is strong rationale to combine temsirolimus (TEM) with Bevacizumab (BEV) for patients with advanced HCC.. A modified two-stage Simon phase II trial was performed with plans to advance to stage 2 if more than 2 patients had confirmed PR or >18 patients were progression free at 6 months out of 25 in stage 1. Toxicity, PFS and overall survival were secondary endpoints. Eligible pts had advanced HCC, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR targeted agents. Patients were treated with temsirolimus 25 mg IV on Days 1, 8, 15, and 22 of a 28 day cycle and bevacizumab 10 mg/kg IV on Days 1 and 15 of the cycle.. Twenty-eight eligible patients were enrolled, 26 evaluable receiving a median of 6.5 cycles (range 1-18). Drug related toxicities were common including cytopenias, fatigue, mucositis, diarrhea and mild bleeds. Dose reductions or discontinuation of TEM were common. Accrual closed for presumed futility after interim analysis of the first 25 evaluable patients showed only one PR and 16/25 were progression-free at 6 months. However, the final data update in March 2013 demonstrated 4 confirmed PRs, a 5th unconfirmed PR and 16 /26 progression-free at 6 months. Median PFS and OS were 7 and 14 months respectively.. This first-line HCC trial evaluating the BEV/TEM doublet reports an ORR of 19 % and OS of 14 months which is favorable but requires further study at a more optimized dose and schedule.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Hepatocellular; Disease-Free Survival; Female; Humans; Liver Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

The combined inhibition of insulin-growth factor type 1 receptor (IGF-1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti-IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial.. Cixutumumab 6 mg/kg and temsirolimus 8 mg/m(2) were administered intravenously once weekly in 4-week cycles to patients <30 years. Temsirolimus was escalated to 10 mg/m(2) for subsequent cycles in patients who did not experience unacceptable first-cycle toxicity. A two-stage design was used to identify a response rate <10 or >35% for each tumor-specific cohort. Tumor tissue was analyzed by immunohistochemistry for potential biomarkers of response.. Forty-three evaluable patients received a median of 2 cycles (range 1-7). No objective responses were observed, and 16% of patients were progression-free at 12 weeks. Dose-limiting toxicity was observed in 15 (16%) of 92 cycles. The most common toxicities were mucositis, electrolyte disturbances, and myelosuppression. The majority of patients receiving a second cycle were not eligible for temsirolimus escalation due to first-cycle toxicity. The lack of objective responses precluded correlation with tissue biomarkers.. Despite encouraging preclinical data, the combination of cixutumumab and temsirolimus did not result in objective responses in this phase II trial of pediatric and young adults with recurrent or refractory sarcoma.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Child; Child, Preschool; Female; Humans; Infant; Male; Sarcoma; Sirolimus; Young Adult

Preclinical data suggest that anti-vascular endothelial growth factor agents combined with mammalian target of rapamycin inhibitors yield synergistic antitumor effects. A phase I trial with a 3+3 dose escalation design of S with T was stopped after the first dose pair led to 2 of 3 patients experiencing dose-limiting toxicity (DLT).. To explore multiple potential dosing pairs of S and T, a 2-stage outcome-adaptive Bayesian dose-finding method was designed. The primary objective was to find the MTD of S and T in patients with advanced renal cell carcinoma. A 3-week treatment cycle consisted of daily S, 2 weeks of treatment, 1 week without treatment, and weekly T.. Twenty patients received study drugs; the median number of previous therapies was 1. The number of patients (S and T doses in mg) was: 2 (S, 12.5; T, 6), 1 (S, 25; T, 12.5), 1 (S, 12.5; T, 8), 8 (S, 12.5 alternate 25; T, 9), 2 (S, 25; T, 6), 2 (S, 25 alternate 37.5; T, 6), 2 (S, 37.5; T, 6), and 2 (S, 37.5; T, 8). Six patients required dose reduction, 3 because of Grade 3 stomatitis, 2 because of Grade 3 thrombocytopenia; the mean number of cycles was 6.6 ± 5.3, the mean time during study was 159 ± 120 days. One patient experienced a DLT in cycle 1 and was nonevaluable, 1 had a partial response, 16 had stable disease, and 2 had progressive disease as best response. There were 21 Grade 3/4 adverse events but no treatment-related deaths.. The MTD of S and T were not determined because of premature trial closure. S 37.5 mg/d, 2 weeks of treatment, 1 week with no treatment, and T 8 mg to 10 mg weekly are close to the MTD.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Carcinoma, Renal Cell; Drug Administration Schedule; Female; Humans; Indoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Pyrroles; Sirolimus; Sunitinib; Treatment Outcome; Young Adult

To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors.. Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle.. Thirty-nine patients, median age 11.8 years (range, 1-21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m(2); (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m(2); (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m(2); and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m(2). Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m(2), the median temsirolimus AUC was 2,946 ng • h/mL (range, 937-5,536) with a median sirolimus AUC of 767 ng • h/mL (range, 245-3,675).. The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m(2), respectively.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Maximum Tolerated Dose; Neoplasms; Sirolimus; Young Adult

There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs.. We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS.. A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%).. The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Squamous cell carcinoma of the head and neck (SCCHN) is a common disease, which has a poor prognosis after failure of therapy. Activation of the PI3K-AKT-mTOR axis is commonly detected in recurrent or metastatic SCCHN, and provided the rationale for the clinical phase II trial in pretreated SCCHN.. The primary end point was the progression-free survival rate (PFR) at 12 weeks. Forty eligible patients have been recruited after failure of platinum chemotherapy and cetuximab. A preplanned futility analysis was successfully passed after ≥1 success was detected in 20 patients. Secondary objectives consisted of progression-free survival (PFS), disease control rate (DCR), overall survival (OS), safety and tolerability, and predictive biomarkers for KRAS, BRAF, PIK3CA mutations, and HPV status. Archived tumor tissue was analyzed for DNA sequence.. A total of 40 patients were eligible. The PFR at 12 weeks was 40% (95% CI 25.0-54.6). The median PFS and OS were 56 days (95% CI 36-113 days) and 152 days (76-256 days), respectively. In 33 assessable patients, disease stabilization occurred in 57.6%, with tumor shrinkage in 13 patients (39.4%). Overall, the treatment was well tolerated. Fatigue (47.5%), anemia (25.0%), nausea (20.0%), and pneumonia (20.0%) were the most common adverse events. Neither PIK3CA mutations, nor HPV status were predictive for success with temsirolimus treatment. No mutations were found for KRAS or BRAF.. Tumor shrinkage and efficacy parameter indicate that inhibition of the PI3K-AKT-mTOR axis was a putative novel treatment paradigm for SCCHN. We could not identify parameters predictive for treatment success of temsirolimus, which underscores the need for refinement of the molecular analysis in future studies.. NCT01172769.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cetuximab; Cisplatin; Disease-Free Survival; Female; Germany; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Sirolimus; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome

Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent.. In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS.. Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively.. Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Dose-Response Relationship, Drug; Feasibility Studies; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome; Vascular Endothelial Growth Factor A

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with r/r follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1-3 prior therapies received Bendamustine (90 mg/m(2), day 1+2) and Rituximab (375 mg/m(2), day 1) with Temsirolimus in doses from 25 to 75 mg added on day 1, 8, 15 of a 28-day cycle. Fifteen (11 MCL, 4 FL) patients were included in the phase I. Median age was 73 years and median pretreatment number was 2. No formal dose-limiting toxicity was observed. Dominant non-hematological side effects were fatigue in 11 (73%), nausea in 9 (60%), mucositis in 7 (47%) and vomiting in 6 patients (40%). Cough, diarrhea, pyrexia and rash were observed in five patients (33%) each. Grade 3/4 events included leukopenia in 6 (40%), neutropenia in 4 (27%) and thrombocytopenia in 2 patients (13%). An objective response was observed in 14/15 patients (93%), including 5 complete response (33%; all MCL). After a median follow-up of 19 months, 67% of patients are without signs of progression. Temsirolimus can be safely added to BR with promising preliminary activity. Recruitment in phase II is ongoing.

Topics: Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Feasibility Studies; Female; Follow-Up Studies; Humans; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Nitrogen Mustard Compounds; Prognosis; Prospective Studies; Remission Induction; Rituximab; Safety; Sirolimus; Survival Rate

The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.. Seventy-one adults with advanced STS who received ⩽ 2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).. There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N = 11) over single agent (N = 10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P = 0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).. While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Sarcoma; Sirolimus; Treatment Outcome; Young Adult

The oncogenic PI3K/Akt/mTOR pathway is frequently activated in HCC. Data on the mTOR inhibitor, temsirolimus, is limited in HCC patients with concomitant chronic liver disease. The objectives of this study were: (1) In phase I, to determine DLTs and MTD of temsirolimus in HCC patients with chronic liver disease; (2) In phase II, to assess activity of temsirolimus in HCC, and (3) to explore potential biomarkers for response.. Major eligibility criteria included histologically confirmed advanced HCC and adequate organ function. In Phase I part of the study, temsirolimus was given weekly in 3-weekly cycle; dose levels were 20 mg (level 1), 25 mg (level 2) and 30 mg (level 3). The MTD was used in the subsequent phase II part; the primary endpoint was PFS and secondary endpoints were response and OS. In addition, exploratory analysis was conducted on pre-treatment tumour tissues to determine stathmin, pS6, pMTOR or p-AKT expressions as potential biomarkers for response. Overall survival and PFS were calculated using the Kaplan-Meier method. Reassessment CT scans were done every 6 weeks. All adverse events were reported using CTCAE v3.. The Phase I part consisted of 19 patients, 2 of 6 patients at level 3 experienced DLT; dose level 2 was determined to be the MTD. The phase II part consisted of 36 patients. Amongst 35 assessable patients, there were 1 PR, 20 SD and 14 PD. Overall, the median PFS was 2.83 months (95% C.I. 1.63-5.24). The median OS was 8.89 months (95% C.I. 5.89-13.30). Grade ≥ 3 that occurred in > 10% of patients included thrombocytopenia (4) and hyponatraemia (4). Exploratory analysis revealed that disease stabilization (defined as CR + PR + SD > 12 weeks) in tumours having high and low pMTOR H-scores to be 70% and 29% respectively (OR 5.667, 95% CI 1.129-28.454, p = 0.035).. In HCC patients with chronic liver disease, the MTD of temsirolimus was 25 mg weekly in a 3-week cycle. The targeted PFS endpoint was not reached. However, further studies to identify appropriate patient subgroup are warranted.. This study has been registered in ClinicalTrials.gov (Id: NCT00321594) on 1 December 2010.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Sirolimus; Treatment Outcome

Squamous cell cancer of the head and neck (SCCHN) is a frequent aggressive malignancy with limited therapeutic options. Increasing evidence suggests that mammalian target of rapamycin (mTOR)-inhibitors might be effective in advanced SCCHN. However, non-invasive biomarkers for early prediction of treatment efficacy are not established in SCCHN. Highly proliferating tumours are characterised by enhanced cell turnover which is associated with enhanced apoptosis. During apoptosis of epithelial cells caspases cleave cytokeratin (CK)-18 can be detected in the blood. In this study we analysed sera from patients with relapsed or metastatic SCCHN patients who have been treated with temsirolimus for caspase-cleaved and total (caspase-cleaved and uncleaved) CK-18 by enzyme-linked immunosorbent assays (ELISAs). In addition, caspase-3 activity was detected by luminometric substrate assay. SCCHN patients revealed higher serum levels of those biomarkers compared to healthy controls. Importantly, patients with short progression-free survival (PFS) showed higher serum levels of caspase-3 activity compared to patients with longer PFS (⩾ 2months). Caspase-3 activity is inversely correlated with PFS. A cut-off value for caspase-3 activity was determined that correctly predicted PFS <2months with a sensitivity of 86% and a specificity of 67%. These data demonstrate that detection of serum caspase-3 activity might be a useful non-invasive biomarker for early identification of SCCHN patients not responding to treatment with novel targeted therapies such as mTOR-inhibitors.

Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Caspases; Disease-Free Survival; Enzyme-Linked Immunosorbent Assay; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Predictive Value of Tests; Protein Kinase Inhibitors; Sirolimus; Squamous Cell Carcinoma of Head and Neck

Cixutumumab (a humanized monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]) and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus were combined in a phase I study of patients with advanced cancer. We investigated the prevalence of metabolic toxicities, their management, and impact on outcome.. The temsirolimus dose was 25 mg or 37.5 mg i.v. weekly with escalating doses of cixutumumab (3, 5, or 6 mg/kg i.v. weekly). No patients with diabetes or hyperlipidemia at baseline were eligible until the expansion cohort. We assessed metabolic derangements in our patient cohort, their management, and their association with tumor shrinkage, time to progression (TTP) and overall survival (OS).. Of the 57 patients analyzed, hyperglycemia was seen in 36 (63%) (grade 1-2: 33 [58%]; grade 3-4: 3 [5%]). The median blood sugar level (fasting and nonfasting) across cohorts was 149 mg/dL (upper limit of normal: 110 mg/dL). No patient developed diabetic ketoacidosis or nonketotic hyperosmolar coma or pancreatitis during treatment. Median maximum triglyceride, cholesterol, and low-density lipoprotein levels achieved were 247 mg/dL (range: 65-702 mg/dL), 243 mg/dL (range: 103-424 mg/dL), and 153 mg/dL (range 50-375 mg/dL), respectively. Higher glucose levels were associated with more RECIST tumor shrinkage (r = -.30 [95% confidence interval: -.52, -.03; p = .03]). There was no association between metabolic toxicities of the mTOR and IGF-1R combination and TTP or OS.. The combination of temsirolimus and cixutumumab was safe and resulted in manageable metabolic toxicities. More tumor shrinkage was seen in patients who developed these adverse events. Although perhaps limited by the small number of patients, no significant association was discerned between hyperglycemia, hypertriglyceridemia, or hypercholesterolemia and TTP or OS.. Results of this study show that the combination of temsirolimus and cixutumumab is safe. The most common side effects, hyperglycemia and hyperlipidemia, are tolerable and manageable. This combination of therapies should not be withheld from diabetic patients and patients with high cholesterol levels. Collaboration between oncologist and endocrinologist allows for individualized treatment and better control of these adverse events, with few dose interruptions and reductions. Supportive care and close monitoring is needed. Those patients who develop hyperglycemia or hypercholesterolemia may benefit more from the drug.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Hypercholesterolemia; Hyperglycemia; Hyperlipidemias; Male; Middle Aged; Neoplasms; Receptor, IGF Type 1; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

On the basis of evidence that resistance to vascular endothelial growth factor (VEGF) receptor inhibition is caused by hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from these classes were hypothesized to improve treatment outcomes relative to single-agent VEGF pathway blockade.. A total of 361 patients with metastatic clear cell renal cell carcinoma were randomly assigned equally to arm A (bevacizumab monotherapy 10 mg/kg intravenously [IV] every 2 weeks), B (bevacizumab 10 mg/kg IV every 2 weeks and temsirolimus 25 mg IV every week), C (bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26), or D (sorafenib 200 mg twice daily and temsirolimus 25 mg IV weekly). Progression-free survival was the primary end point.. Among 331 eligible treated patients, median PFS was 7.5 months for bevacizumab alone (90% CI, 5.8 to 10.8 months), 7.6 months for bevacizumab plus temsirolimus (90% CI, 6.7 to 9.2 months), 9.2 months for bevacizumab plus sorafenib (90% CI, 7.5 to 11.4 months), and 7.4 months for sorafenib plus temsirolimus (90% CI, 5.6 to 7.9 months). Hazard ratios from stratified Cox proportional hazards models were 1.01, 0.89, and 1.07 (with respective P values of .95, .49, and .68) for the three combinations, respectively, compared with bevacizumab alone. Adverse events did not differ significantly among treatment arms.. The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; raf Kinases; Sirolimus; Sorafenib; TOR Serine-Threonine Kinases; Treatment Outcome; Vascular Endothelial Growth Factor A

Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B-cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models.. The authors conducted a single-arm, phase 2 trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle.. Of 39 patients who received treatment, 3 achieved a complete response (7.7%; 95% confidence interval [CI], 1.6%-21%), and 9 had a partial response (PR) (23%; 95% CI, 11%-39%). Thus, the overall response rate (12 of 39 patients) was 31% (95% CI, 17%-48%), and the median progression-free survival was 4.7 months (95% CI, 2.1-7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a complete response. There were no unexpected toxicities from the combination.. The current results demonstrate that the combination of a mammalian target of rapamycin inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. Further studies with this combination are warranted in specific subtypes of NHL.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease-Free Survival; Female; Humans; Incidence; Lymphoma, Non-Hodgkin; Male; Sirolimus; Wisconsin

Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells--G1, S, and G2/M.. Temsirolimus (G1 inhibitor), topotecan (S inhibitor), and bortezomib (G2/M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen.. Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m(2) IV D1, 8; and bortezomib 0.6 mg/m2 IV D1, 4, 8, 11 [DOSAGE ERROR CORRECTED] of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G2/M and S phases to G1 phase and the quiescent G0 phase. Eighteen percent of subjects (11/62) achieved partial response (n = 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n = 9).. Combining drugs with inhibitory activity of G1 phase, S phase, and G2/M phase is safe and warrants further evaluation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Computer Simulation; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Models, Biological; Molecular Targeted Therapy; Neoplasms; S Phase Cell Cycle Checkpoints; Sirolimus; Texas; Time Factors; Topotecan; Treatment Outcome; Young Adult

Temsirolimus maintenance therapy after docetaxel induction chemotherapyis safe in patients with castration-resistant prostate cancer, although biochemical or tumor responses are rare;does not diminish quality of life; anddelays radiological and/or symptomatic progression by approximately 6 months.. No standard therapy is available for men with castration-resistant prostate cancer (CRPC) who have responded to docetaxel and do not yet have disease progression. Hence, we designed a single-arm phase II trial to explore whether the mTOR inhibitor temsirolimus can maintain the response to docetaxel without compromising quality of life.. After successful docetaxel induction (75 mg/m(2) every 3 weeks; 6-10 cycles), 21 CRPC patients underwent temsirolimus maintenance treatment (25 mg weekly; 4 weeks per cycle). The primary endpoint was the time to treatment failure (TTTF) (i.e., radiological and/or symptomatic progression). The secondary endpoints included the tumor response rate (RECIST 1.0), safety (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0), quality of life (Functional Assessment of Cancer Therapy-Prostate [FACT-P]), pain (Present Pain Intensity [PPI] scale), prostate-specific antigen (PSA) parameters, including time to PSA progression (TTPP) according to Prostate Cancer Clinical Trials Working Group criteria, and serial enumeration of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs).. Patients received a median of 7 cycles of temsirolimus (range, 1-28), resulting in a median TTTF of 24.3 weeks (95% confidence interval [CI], 16.1-33.0), 1 partial tumor response (4.8%), 1 PSA response (4.8%), and a median TTPP of 12.2 weeks (95% CI, 7.8-23.9). Grade 3-4 adverse events were infrequent, and FACT-P and PPI scores remained stable during treatment. CECs did not predict clinical benefit, and CEPs were not consistently detectable.. Temsirolimus maintenance therapy after successful docetaxel induction is feasible, does not adversely affect quality of life, and, in this exploratory single-arm phase II study, resulted in a median TTTF of 24.3 weeks.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Sirolimus; Taxoids; Treatment Outcome

Temsirolimus (TEMSR) was approved for treating advanced renal cell carcinoma (RCC) in 2007. Based on the data from a single phase 3 trial, it is recommended explicitly as first-line therapy for patients with a poor clinical prognosis.. The aim of this prospective multicentre trial (STARTOR) was to examine the effectiveness of TEMSR in daily clinical practice with a broader indication in the treatment of metastatic RCC.. Metastatic RCC patients treated with 25mg of TEMSR weekly were submitted to a prospective systematic evaluation and follow-up in 87 German centres between January 2008 and October 2011 using standardised procedures.. All data were centrally analysed by an independent clinical research organisation.. This interim analysis of the STARTOR study included 386 patients. The observed toxicity was tolerable, the median dose intensity was 91% (interquartile range: 79-100%), and the median treatment duration was 20.1 wk (95% confidence interval [CI], 17.0-23.3 wk). Clinical benefit was seen in 157 patients (40.7%); the median progression-free and overall survival were 4.9 mo (95% CI, 4.2-5.6) and 11.6 mo (95% CI, 9.3-13.9), respectively. The effectiveness of TEMSR did not differ significantly in relation to the patient's age, histologic RCC subtype, or line of treatment. The major limitations were the noninterventional study design, limited information about Memorial Sloan-Kettering Cancer Center risk factors and detailed toxicity, and the lack of central radiologic review.. TEMSR is an effective and largely well-tolerated treatment alternative for metastatic RCC patients in daily clinical practice, irrespective of the patient's age, histologic RCC subtype, or line of treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Male; Middle Aged; Prospective Studies; Sirolimus; Survival Rate

Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer.. Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed.. Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% (P = .14).. No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents.

Topics: Adult; Aged; Aged, 80 and over; Animals; Class I Phosphatidylinositol 3-Kinases; Endometrial Neoplasms; Female; Humans; Middle Aged; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

mTOR inhibitors have activity in pediatric tumor models. A phase I trial of the mTOR inhibitor temsirolimus (TEM) with irinotecan (IRN) and temozolomide (TMZ) was conducted in children with recurrent/refractory solid tumors, including central nervous system (CNS) tumors.. Escalating doses of intravenous (IV) TEM were administered on days 1 and 8 of 21-day cycles. IRN (50 mg/m(2)/dose escalated to a maximum of 90 mg/m(2)/dose) and TMZ (100 mg/m(2)/dose escalated to a maximum of 150 mg/m(2)/dose) were administered orally (PO) on days 1-5. When maximum tolerated doses (MTD) were identified, TEM frequency was increased to weekly.. Seventy-one eligible pts (median age 10.9 years, range 1.0-21.5) with neuroblastoma (16), osteosarcoma (7), Ewing sarcoma (7), rhabdomyosarcoma (4), CNS (22) or other (15) tumors were enrolled. Dose-limiting hyperlipidemia occurred in two patients receiving oral corticosteroids. The protocol was subsequently amended to preclude chronic steroid use. The MTD was identified as TEM 35 mg/m(2) IV weekly, with IRN 90 mg/m(2) and TMZ 125 mg/m(2) PO on days 1-5. At higher dose levels, elevated serum alanine aminotransferase and triglycerides, anorexia, and thrombocytopenia were dose limiting. Additional ≥ grade 3 regimen-related toxicities included leukopenia, neutropenia, lymphopenia, anemia, and nausea/vomiting. Six patients had objective responses confirmed by central review; three of these had sustained responses through ≥ 14 cycles of therapy.. The combination of TEM (35 mg/m(2)/dose IV weekly), IRN (90 mg/m(2)/dose days 1-5) and TMZ (125 mg/m(2)/dose days 1-5) administered PO every 21 days is well tolerated in children. Phase 2 trials of this combination are ongoing.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Child; Child, Preschool; Dacarbazine; Female; Follow-Up Studies; Humans; Infant; Irinotecan; Male; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Remission Induction; Sirolimus; Temozolomide; Young Adult

To prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC).. In a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear-cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25 mg intravenously, weekly) or IFN (9 MIU subcutaneously thrice weekly) with bevacizumab (10 mg/kg intravenously, every 2 weeks). The primary end point was independently assessed progression-free survival (PFS).. Median PFS in patients treated with temsirolimus/bevacizumab (n = 400) versus IFN/bevacizumab (n = 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR], 1.1; 95% CI, 0.9 to 1.3; P = .8). There were no significant differences in overall survival (25.8 ν 25.5 months; HR, 1.0; P = .6) or objective response rate (27.0% ν 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) -15 and FKSI-Disease Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade ≥ 3 adverse events more common (P < .001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2.. Temsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Interferon-alpha; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Proportional Hazards Models; Prospective Studies; Sirolimus; Time Factors; Treatment Outcome; Young Adult

This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib.. In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non-clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points.. Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies.. In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Female; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib; Time Factors; TOR Serine-Threonine Kinases; Treatment Failure; Young Adult

With an increasing choice of new treatment options, the management of side effects to maintain a chosen treatment if likely to be effective on the tumor remains important. The perception of side effects however varies between the physician and the patient, leading to possible wrong assumptions on tolerability that result in dose modifications, which may ultimately affect effectiveness. The aim was to assess fatigue in patients with advanced or metastatic renal cell carcinoma (RCC) by comparing the evaluation of the physician to the one provided by their respective patient. In addition, we aimed to assess possible influences of fatigue on parameters of quality of life.. Patients receiving systemic treatment for advanced RCC and their physicians were questioned independently regarding incidence and severity of fatigue and its effect on quality of life.. Both physicians and patients completed 98 matching questionnaires. Patients were treated with sunitinib, sorafenib, bevacizumab combined with interferon alpha, temsirolimus, everolimus, or interferon alpha alone. Incidence and severity of fatigue was differently assessed by patients and physicians, with fatigue being more severe when reported by the patient. The severity of fatigue increased with progressing treatment lines. Quality of life was significantly lower in patients experiencing fatigue compared with patients without fatigue. Emotional, functional, and physical well-being were all affected by fatigue, the latter being the most affected subscale. Social well-being was least affected.. Fatigue is a complex and cumulative condition of patients treated for advanced RCC, and it considerably affects patient's quality of life. As many of its underlying causes may be treated, the divergent perception of occurrence and severity of fatigue should be integrated in treatment concepts. The active role of the patient in helping to manage ailments through assessment should be implemented when optimizing treatment of RCC.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Cross-Sectional Studies; Everolimus; Fatigue; Female; Humans; Incidence; Indoles; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Physicians; Pyrroles; Quality of Life; Self Report; Sirolimus; Sorafenib; Sunitinib; Surveys and Questionnaires

Human epidermal growth factor (HER) -mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors.. This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses.. Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway.. The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Female; Gene Amplification; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Nausea; Neoplasms; Phosphatidylinositol 3-Kinases; Quinolines; Receptor, ErbB-2; Signal Transduction; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases; Treatment Outcome

The addition of targeted agents to thoracic radiation has not improved outcomes in patients with locally advanced non-small-cell lung cancer (NSCLC). To improve cure rates in locally advanced NSCLC, effective targeted therapies need to be identified that can be given safely with radiation therapy. Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway and has single-agent activity in lung cancer. Inhibition of the mTOR pathway has been found to augment the cytotoxic effect of radiation in preclinical studies. There is scant clinical experience with mTOR inhibitors and radiation.. This was a phase I study evaluating the combination of temsirolimus with thoracic radiation in patients with NSCLC.. Ten patients were enrolled in the study. The dose-limiting toxicities included sudden death, pneumonitis, and pulmonary hemorrhage. The maximum tolerated dose of temsirolimus that could be administered safely with concurrent radiotherapy (35 Gy in 14 daily fractions) was 15 mg intravenously weekly. Of the 8 evaluable patients, 3 had a partial response and 2 had stable disease.. The combination of temsirolimus 15 mg weekly and thoracic radiation is well tolerated and warrants further investigation, perhaps in a molecularly defined subset of patients.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Radiotherapy Dosage; Sirolimus; Survival Rate

Oncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial.. Genomic profiling with clinical next generation sequencing was performed on the FoundationOne™ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199).. The histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial.. The patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to sorafenib-based combination therapy.

Topics: Antibodies, Monoclonal, Humanized; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Humans; Immunohistochemistry; Middle Aged; Molecular Targeted Therapy; Niacinamide; Oncogene Proteins, Fusion; Phenylurea Compounds; Proto-Oncogene Proteins B-raf; S100 Proteins; Sarcoma; Sequence Analysis, DNA; Sirolimus; Sorafenib; TOR Serine-Threonine Kinases; Treatment Outcome

To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.. Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.. We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.. There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.. Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Megestrol Acetate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Sirolimus; Tamoxifen

Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.. We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.. Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.. Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Erlotinib Hydrochloride; Female; Follow-Up Studies; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Quinazolines; Sirolimus; Survival Rate; Tissue Distribution; Young Adult

Pegylated liposomal doxorubicin (PLD) is active in breast, endometrial, and ovarian cancer. Preclinical data suggest that the combination of PLD with a mammalian target of rapamycin (mTOR) inhibitor has an additive effect. The safety and recommended phase two dose (RPTD) of temsirolimus in combination with PLD were assessed. (18) F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT was performed for early response monitoring. Nineteen patients with advanced breast, endometrial, and ovarian cancer were treated with increasing doses of temsirolimus (10, 15, or 20 mg once weekly) and PLD (30 or 40 mg/m(2) once every 4 weeks). PLD was initiated 2 weeks after start of temsirolimus. FDG-PET/CT was performed at baseline, after 2 and 6 weeks. Standardized uptake values (SUV), metabolic volume, and total lesion glycolysis (TLG, SUV × metabolic volume) were calculated. The RPTD was 15 mg temsirolimus and 40 mg/m(2) PLD. Dose-limiting toxicities (DLT) were thrombocytopenia grade 3 with nose bleeding and skin toxicity grade 3. Most frequent treatment-related toxicities were nausea, fatigue, mucositis, and skin toxicity. Changes in TLG after 2 weeks predicted partial response (PR) after 10 weeks (p = 0.037). A rise in SUV between the second and sixth week predicted progression (PD) (p = 0.034) and was associated with worse progression free survival (PFS) (HR 1.068; p = 0.013). The RPTD was established at 15 mg temsirolimus weekly and PLD 40 mg/m(2) once every 4 weeks and the combination was safe. Early response evaluation with FDG-PET/CT may predict subsequent radiological PR and PD. This trial is registered under number NCT0098263.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Endometrial Neoplasms; Female; Fluorodeoxyglucose F18; Glycolysis; Humans; Middle Aged; Multimodal Imaging; Ovarian Neoplasms; Polyethylene Glycols; Positron-Emission Tomography; Protein Kinase Inhibitors; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Metformin; Middle Aged; Mucositis; Niacinamide; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. METHODS. Four cohorts of patients received weekly bryostatin-1 (20 μg/m²) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles.. Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 μg/m² every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥ 80 months, respectively. Partial responses were seen in both clear cell and papillary histology.. This combination of 37.5 mg of temsirolimus with 20 μg/m² of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Carcinoma, Renal Cell; Drug Administration Schedule; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Protein Kinase C; Protein Kinase Inhibitors; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Pre-clinical findings suggest that combination treatment with bevacizumab and temsirolimus could be effective against malignant pediatric central nervous system (CNS) tumors.. Six pediatric patients were treated as part of a phase I trial with intravenous temsirolimus 25 mg on days 1, 8, 15, and bevacizumab at 5, 10, or 15 mg/kg on day 1 of each 21-day cycle until disease progression or patient withdrawal.. The median patient age was six years (range=3-14 years). The primary diagnoses were glioblastoma multiforme (n=2), medullobalstoma (n=2), pontine glioma (n=1) and ependymoma (n=1). All patients had disease refractory to standard-of-care (2-3 prior systemic therapies). Grade 3 toxicities possibly related to drugs used occurred in two patients: anorexia, nausea, and weight loss in one, and thrombocytopenia and alanine aminotransferase elevation in another. One patient with glioblastoma multiforme achieved a partial response (51% regression) and two patients (with medulloblastoma and pontine glioma) had stable disease for four months or more (20 and 47 weeks, respectively). One other patient (with glioblastoma multiforme) showed 18% tumor regression (duration=12 weeks).. The combination of bevacizumab with temsirolimus was well-tolerated and resulted in stable disease of at least four months/partial response in three out of six pediatric patients with chemorefractory CNS tumors.

Topics: Adolescent; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Central Nervous System Neoplasms; Child; Child, Preschool; Humans; Magnetic Resonance Imaging; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

Bevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors.. We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus.. Median age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) > 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD > 6 months/PR.. Bevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD > 6 months/PR, suggesting that this combination warrants further study.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bevacizumab; Carcinoma; Fatigue; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Mucositis; Neutropenia; Ovarian Neoplasms; Sirolimus; Thrombocytopenia; Uterine Cervical Neoplasms

This study aimed to determine the maximum-tolerated dose and dose-limiting toxicities of pegylated liposomal doxorubicin (PLD) in combination with temsirolimus (T) in patients with refractory solid tumors. Using a standard "3+3" dose escalation design, 23 patients were enrolled in three dosing cohorts in this phase I study. The starting dose level was PLD at 30 mg/m(2) every 4 weeks and T at 20 mg weekly. Pharmacokinetics (PK) of doxorubicin were evaluated for patients in the expansion cohort. The most common treatment-related adverse events of all grades were mucositis/stomatitis (69.6%), anorexia (52.2%), thrombocytopenia (52.2%), and fatigue (47.8%). The recommended doses of this combination for phase II studies are 25 mg/m(2) PLD and 25 mg T. PK analyses suggested increased exposure of doxorubicin in this combination regimen compared to doxorubicin administered as a single agent, possibly due to PK drug interactions. Out of 18 patients evaluable for a treatment response, two had partial responses (PR) (breast cancer and hepatocellular carcinoma) and six had stable disease (SD). Two patients remained on treatment for more than 1 year. The combination of PLD and T is tolerable, and the treatment resulted in clinical benefit. The combination regimen should be further explored in appropriate tumor types.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Doxorubicin; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Polyethylene Glycols; Prognosis; Safety; Sirolimus; Tissue Distribution

Pegylated liposomal doxorubicin (PLD) is used to treat patients with breast and gynecological cancers. In order to optimize treatment with PLD, we assessed the prognostic and predictive factors for efficacy of PLD.. Seventeen patients treated with PLD 30 or 40 mg/m(2) underwent pharmacokinetic sampling during the first cycle of treatment. PLD exposure was calculated. An univariate analysis was performed with the variables: hand-foot syndrome, mucositis, rash, neutropenia, age, tumor type, number of previous therapies, ECOG performance status and progression-free survival (PFS). Candidate variables with p ≤ 0.1 were selected for the multivariate analysis.. Based on the results of the multivariate analysis, the PLD exposure (log AUC) was higher in patients who experienced rash (p = 0.002) and mucositis (p = 0.001) compared to those who did not have these adverse events. The development of hand-foot syndrome was significantly related to a lower risk of disease progression (HR 0.1; 95 % CI 0.02-0.64). Patients with an ECOG status of 0 had a longer PFS than the patients with an ECOG status of 1 (HR 5.4; 95 % CI 1.3-22.8). Moreover, PLD exposure (ln AUC) was also positively related to PFS (HR 0.001; 95 % CI 0.00-0.42).. The extent of the exposure to PLD was correlated with more adverse events and longer PFS. This has important clinical implications, since dose reductions or interruptions might thus negatively affect treatment outcomes. More attention should be paid to preventive and supportive measures of adverse events of PLD to keep the exposure to PLD as high as possible.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Area Under Curve; Breast Neoplasms; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Endometrial Neoplasms; Female; Hand-Foot Syndrome; Humans; Middle Aged; Mucositis; Multivariate Analysis; Ovarian Neoplasms; Polyethylene Glycols; Sirolimus; Treatment Outcome; Young Adult

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Dose-Response Relationship, Drug; Female; Fluorodeoxyglucose F18; Humans; Hydroxychloroquine; Male; Melanoma; Middle Aged; Neoplasm Staging; Neoplasms; Positron-Emission Tomography; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Vacuoles

We conducted this trial to determine the maximum tolerated dose (MTD) of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma.. A standard phase I cohort of three study design was utilized. The fixed doses of rituximab and cladribine were 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. There were five planned temsirolimus i.v. dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1, 8 and 15; and 25 mg days 1, 8, 15, and 22.. Seventeen patients were treated: three each at levels 1-4 and five at dose level 5. The median age was 75 years (52-86 years). Mantle Cell International Prognostic Index (MIPI) scores were low in 6% (1), intermediate in 59% (10), and high in 35% (6) of patients. Five patients were treated at level 5 without dose limiting toxicity. Hematologic toxicity was frequent: grade 3 anemia in 12%, grade 3 thrombocytopenia in 41%, grade 4 thrombocytopenia in 24%, grade 3 neutropenia in 6%, and grade 4 neutropenia in 18% of patients. The overall response rate (ORR) was 94% with 53% complete response and 41% partial response. The median progression-free survival was 18.7 months.. Temsirolimus 25 mg i.v. weekly may be safely added to rituximab and cladribine at 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma.. NCT00787969.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Rituximab; Sirolimus

To determine the maximal tolerated dose (MTD) of the combination of weekly temsirolimus and every other week vinorelbine in patients with advanced or refractory solid tumors.. Patients were treated with intravenous temsirolimus on days 1, 8, 15, and 22 and intravenous vinorelbine on days 1 and 15. Cycles were repeated every 28 days.. Nineteen patients were enrolled in the study. Tumor types included lung (5), prostate (2), neuroendocrine of pancreas (1), bladder (2), uterus (3), cervix (4), and vagina (2). All patients had received prior chemotherapy. Four patients were enrolled to dose level I, nine to dose level II, and six to dose level III. Six patients were inevaluable and replaced. Fifty-seven total cycles were administered. There was 1 dose-limiting toxicity at level II (grade 3 anorexia/dehydration) and 2 at level III (grade 3 hypokalemia; grade 4 neutropenia). Two patients died at dose level III; one was study-related with grade 4 neutropenia. Grade 3/4 toxicities observed during the first cycle included neutropenia (2), anemia (1), anorexia (1), dehydration (1), hyperglycemia (1), hypertriglyceridemia (1), and hypokalemia (1). Best response included two patients (prostate and non-small cell lung cancer) with partial response and eight patients with stable disease with median duration of best response of 3.2 months.. Temsirolimus 25 mg given days 1, 8, 15, and 22 in combination with vinorelbine 20 mg/m(2) given days 1 and 15 every 4 weeks was found to be the MTD. This dose combination is considered feasible in phase II trials.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Feasibility Studies; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Sirolimus; Treatment Outcome; Vinblastine; Vinorelbine

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy without an available effective systemic chemotherapy. Insulin growth factor 2 (IGF-2) overexpression leading to the activation of the IGF-1 receptor (IGF-1R)/mammalian target of rapamycin (mTOR) pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at IGF-1R was combined with temsirolimus on the basis of preclinical data.. Patients received cixutumumab, 3-6 mg kg(-1) intravenously (IV) weekly, and temsirolimus, 25-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks.. Twenty-six patients were enrolled (13 (50%) men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolaemia (31%), hypertriglyceridemia (35%), and hyperglycaemia (31%). In all, 11 of 26 patients (42%) achieved stable disease (SD) >6 months (duration range=6-21 months) with 3 of the 11 having received a prior IGF-1R inhibitor.. Cixutumumab combined with temsirolimus was well tolerated and >40% of patients achieved prolonged SD.

Topics: Adrenocortical Carcinoma; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Male; Middle Aged; Sirolimus; Young Adult

Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.. We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015.. Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%).. The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination.. National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Neoplasm Grading; Protein Kinase Inhibitors; Receptor, IGF Type 1; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases

Patients with chemotherapy refractory metastatic colorectal cancer and KRAS mutations have no effective treatment option. The present study evaluated the efficacy of temsirolimus in chemotherapy refractory mCRC with KRAS mutations. Furthermore, we wanted to investigate if resistance to temsirolimus could be reversed by the addition of irinotecan. Finally, we analyzed pre-treatment blood samples for KRAS mutations to investigate the association between quantitative measures of KRAS mutated alleles and clinical outcome.. Patients received weekly temsirolimus 25 mg until progression. Thereafter patients were treated with combination therapy comprising biweekly irinotecan 180 mg/m(2) and weekly temsirolimus. A polymerase chain reaction method was used to quantify the KRAS mutated alleles in plasma (pKRAS).. Sixty-four patients were included. Treatment was well tolerated. Thirty-eight percent achieved stable disease on monotherapy and 63% on combination therapy. Four and eight patients had a minimal response, respectively. Median overall survival was 160 days. Median time to progression was 45 and 84 days, respectively. The concordance between KRAS status in tumor and plasma was 82%. All patients with tumor reduction had low levels of pKRAS. Patients with high pKRAS had a 77% risk of early progression on monotherapy compared to 43% in patients with lower levels. Multivariate survival analysis confirmed that pKRAS was a strong prognostic factor.. Temsirolimus has limited efficacy in chemotherapy resistant KRAS mutant disease, but plasma KRAS quantification is a strong predictor of outcome.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Irinotecan; Male; Middle Aged; Mutation; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Sirolimus; Treatment Outcome

Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC).. Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD.. Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients.. The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Topics: Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biomarkers, Tumor; Carcinoma, Hepatocellular; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplastic Cells, Circulating; Niacinamide; Phenylurea Compounds; Protein Precursors; Prothrombin; Sirolimus; Sorafenib; Treatment Outcome

Bevacizumab combined with chemotherapy has recently shown promising efficacy in recurrent high-grade glioma. Phosphatase and tensin homolog (PTEN) mutation in glioblastoma multiforme (GBM) patients causes abnormally high activity of the pathways of Phosphatidylinositide 3-kinases (PI3K), Protein Kinase B (AKT), and the mammalian target of rapamycin (mTOR) and is associated with unfavorable prognosis. Temsirolimus, an mTOR inhibitor, has been well-tolerated in monotherapy, but with limited effects. The combination of temsirolimus and antibodies to vascular endothelial factor (VEGF) has not yet been investigated, but with the hypothesis that temsirolimus might provide complimentary therapeutic benefit in combination with bevacizumab, we included patients with progressive GBM after bevacizumab in an open phase II study.. Adult patients with GBM recurrence after standard temozolomide chemoradiotherapy and bevacizumab-containing second-line therapy, received temsirolimus (25 mg i.v.) on days 1 and 8 and bevacizumab (10 mg/kg) on day 8, every two weeks. Assessments were performed every eight weeks. Blood samples for biomarkers were collected weekly for the first eight weeks and at progression. The primary end-point was median progression-free survival (PFS) and secondary end-points were radiographic response, overall survival (OS), and safety of the bevacizumab-temsirolimus combination.. Thirteen patients were included, whereof three went off-study during the first four weeks and were replaced. The trial was terminated at 13 patients, according to the planned two-stage design, because 0/10 patients obtained partial remission (PR). Two out of 10 patients obtained radiological stable disease (SD). The median PFS survival was eight weeks, and OS was 15 weeks. One patient had an serious adverse event (SAE) with a hypersensitive reaction to temsirolimus; overall, side-effects were mild, and the most common grade III side-effect was hypercholesterolaemia (4/10). Other grade III side-effects included hypertriglyceridaemia (1/10), thrombocytopenia (1/10), infection (1/10), hypertension (1/10), and hyperglycemia (1/10).. Temsirolimus can be safely administered in combination with bevacizumab. This study failed to detect activity of such a combination in patients with progressive GBM beyond bevacizumab therapy.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Sirolimus; Survival Rate; Young Adult

The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose (MTD) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies. A 3 + 3 Phase I design was chosen. Temsirolimus and Cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34-72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be Cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Receptor, IGF Type 1; Sirolimus

A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma.. Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood.. Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAF(WT) tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P < 0.001), and decreased mitotic rate (Ki67(+)) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4(+)FoxP3(+) cells.. These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAF(wt) melanoma. Mixed effects on immunologic function also support combination with immune therapies.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biopsy; Female; GTP Phosphohydrolases; Humans; Ki-67 Antigen; Male; Melanoma; Membrane Proteins; Middle Aged; Mutation; Neoplasm Staging; Phosphoproteins; Proto-Oncogene Proteins B-raf; Sirolimus; Treatment Outcome

HPV infection has been associated with deregulation of the PI3K-Akt-mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix.. Temsirolimus 25mg i.v. was administered weekly in 4 week cycles. One response among the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumor tissue.. Thirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5 months (range 2.4-12.0mo)]. The 6-month progression free survival rate was 28% (95% CI: 14-43%). The median progression free survival was 3.52 months [95% CI (1.81-4.70)]. Adverse effects were mild-moderate in most cases and similar to other temsirolimus studies. No toxicity>grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability.. Single agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified.

Topics: Adult; Aged; Antineoplastic Agents; Class I Phosphatidylinositol 3-Kinases; Disease-Free Survival; Female; Humans; Immunohistochemistry; Middle Aged; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases; Uterine Cervical Neoplasms

Inhibition of either vascular endothelial growth factor receptor or mammalian target of rapamycin (mTOR) signaling improves outcomes in patients with several advanced solid tumors. We conducted a phase I trial of temsirolimus with pazopanib to investigate the feasibility of simultaneous 'vertical inhibition' of vascular endothelial growth factor receptor and mTOR pathways. Patients with advanced solid tumors, no previous pazopanib or mTOR inhibitor, good performance status, and acceptable end-organ function were eligible. In a typical 3+3 escalation design starting at temsirolimus 15 mg by an intravenous infusion weekly and pazopanib 400 mg orally daily, we defined dose-limiting toxicity (DLT) as attributable grade 3 or higher nonhematologic adverse events in the first 28-day cycle and the maximum tolerable dose as the maximum dose level at which less than two patients experienced DLT. At the initial dose level, two patients had four DLTs (anorexia, fatigue, hyponatremia, and hypophosphatemia). After reduction to temsirolimus 10 mg intravenous infusion weekly and pazopanib 200 mg orally daily, one of three patients had DLT (fatigue) and the first patient in the subsequent expansion had dose-limiting hypophosphatemia. Attributable grade 3 or higher adverse events in more than one patient included leukopenia, neutropenia, fatigue, and hypophosphatemia. Tumor reduction not fulfilling the RECIST criteria for partial response was the best response in four of seven evaluable patients. The combination of temsirolimus and pazopanib was not feasible at clinically meaningful doses in this population because of constitutional and electrolyte disturbances.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases

Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor.. Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort.. Of 27 patients treated, 20 patients had received ≥ 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ≤ 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus.. In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome

The current standard treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL) primarily consists of intensified salvage therapy and, if the disease is chemo-sensitive, high dose therapy followed with autologous stem cell transplantation. In the rituximab era however, this treatment approach has shown only limited benefit. In particular, patients relapsing after rituximab-containing primary treatment have an adverse prognosis, especially if this occurs within the first year after therapy or if the disease is primarily refractory. Therefore there is an ultimate need for improved salvage treatment approaches.. The STORM study is a prospective, multicentre phase I/II study to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to the standard therapy rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. The primary objective of the phase I of the trial is to establish the maximum tolerated dose (MTD) of temsirolimus in combination with rituximab and DHAP. The secondary objective is to demonstrate that stem cells can be mobilized during this regimen in patients scheduled to proceed to high dose therapy. In phase II, the previously established maximum tolerated dose of temsirolimus will be used. The primary objective is to evaluate the overall response rate (ORR) in patients with relapsed DLBCL. The secondary objective is to evaluate progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by an analysis of lymphoma subtypes determined by gene expression analysis (GEP).. The STORM trial evaluates the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. It also might identify predictive markers for this treatment modality.. ClinicalTrials.gov NCT01653067.

Topics: Adult; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cytarabine; Dexamethasone; Disease-Free Survival; Feasibility Studies; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Research Design; Rituximab; Salvage Therapy; Sirolimus; TOR Serine-Threonine Kinases

Phosphatase and tensin homologue (PTEN) loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 kinase pathway. Temsirolimus blocks mammalian target of rapamycin (mTOR)/target of rapamycin complex 1 (TORC1), a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer (mCRPC) is unknown.. We conducted a single-arm trial of weekly intravenous temsirolimus administration in men with chemorefractory mCRPC who had ≥ 5 circulating tumor cells (CTCs) at baseline. The primary end point was the change in CTCs at 8 weeks; secondary end points were composite progression-free survival (PFS) (excluding prostate-specific antigen [PSA]), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus.. Eleven patients were accrued out of a planned 20; the trial was stopped prematurely because of lack of efficacy/feasibility. Median age was 61 years, with 55% African-Americans and 36% Caucasian patients. Median baseline PSA level was 390 ng/dL, median baseline number of CTCs was 14 cells; 50% of patients had pain, and 63% had undergone ≥ 2 previous chemotherapy regimens. Median CTC decline was 48% and 3 patients experienced decline in CTCs to < 5. However, 73% of men had a persistently unfavorable number of CTCs (≥ 5) and only 1 patient had a ≥ 30% PSA decline. Median PFS was 1.9 months (95% confidence interval [CI], 0.9-3.1) and median overall survival (OS) was 8.8 months (95% CI, 3.1-15.6). Toxicities included grade 4 hypophosphatemia and central nervous system (CNS) hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia.. Temsirolimus lacked sufficient clinical activity in men with mCRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors.

Topics: Adult; Aged; Bone Neoplasms; Disease Progression; Disease-Free Survival; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Multiprotein Complexes; Neoplastic Cells, Circulating; Phosphoinositide-3 Kinase Inhibitors; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Sirolimus; Survival; TOR Serine-Threonine Kinases; Treatment Failure

New targeted therapeutics approved for metastatic renal cell carcinoma (mRCC) offer multiple options in each line of therapy; however, there are few prospective data beyond the first-line settings, and overall comparative effectiveness data are limited. In the targeted therapy era, progression-free survival (PFS) has been the most common regulatory end point for demonstrating the benefit of new therapies.. Drawing on a joint community-academic retrospective mRCC registry, we analyzed all patients who had undergone at least 1 line of systemic therapy (N = 325) for PFS. Patients were grouped according to treatment choice (sorafenib, sunitinib, temsirolimus, everolimus, and "other") for up to 3 lines of therapy. PFS by treatment choice and line of therapy was evaluated using Kaplan-Meier and Cox regression analyses.. PFS was longest in patients treated with sunitinib in the first and second lines of therapy. First-line PFS for sorafenib, sunitinib, temsirolimus, everolimus, and "other" was 6.9, 8.9, 4.2, not analyzed (too few patients), and 10.8 months, respectively. Second-line PFS was 4.6, 7.0, 3.2, 3.8, and 4.1 months, respectively. Third-line PFS was 4.5, 4.6, 9.9, 4.2, and 2.9, months, respectively. The risk of progression in patients treated with temsirolimus was about twice that of patients treated with sunitinib in the first and second lines of therapy.. Patients treated with sunitinib had the longest PFS in the first and second lines of therapy. PFS from practice-based data appear consistent with trial-based expectations; however, practice variation was still evident.

Topics: Carcinoma, Renal Cell; Cohort Studies; Disease-Free Survival; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus.. Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations.. Seventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted.. RO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.

Topics: Adult; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzazepines; Calcium-Binding Proteins; Fatigue; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Membrane Proteins; Middle Aged; Mucositis; Neoplasms; Protein Kinase Inhibitors; Receptor, Notch3; Receptors, Notch; Serrate-Jagged Proteins; Sirolimus

Temsirolimus (TEM) has recently shown activity (NCIC CTG phase II trial) in endometrial cancer (EC). Despite EC having a high rate of PTEN mutation, in this trial activity was independent of PTEN and other molecular markers. We explored whether treatment related toxicity occurring in cycle one was predictive of outcomes.. Patients were those enrolled on two sequential phase II studies of the NCIC CTG that evaluated single agent TEM in women with recurrent or metastatic chemotherapy naïve or treated EC. An exploratory landmark analysis examined the relationship between early treatment related toxicities as well as prior chemotherapy and efficacy outcomes (response, progression, and tumor size shrinkage) in univariate and multivariate analyses. The relationship between molecular markers and outcomes was also reexamined in patients.. Mucositis, diarrhea, decreased absolute neutrophil count, as well as elevated glucose, or cholesterol were not independent predictors of response or progression. Highest fasting triglyceride predicted for a 3.5% tumor shrinkage from baseline. Women previously treated with chemotherapy were at 7.37 times greater risk of progression and experienced 20.9% increased tumor growth compared to chemotherapy naïve women. Molecular markers were not predictors of response or progression.. Except for elevation in fasting triglyceride being associated with minimal tumor shrinkage, no other relationship between efficacy and TEM induced adverse events was found. mTOR inhibition activity in EC seems greatest in chemo-naïve patients. Future studies of mTOR inhibitors in EC should focus on women without prior chemotherapy while continuing to explore molecular mechanisms of benefit.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Adenosquamous; Disease Progression; Drug Administration Schedule; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies; Sirolimus

Lenalidomide, an immunomodulatory and anti-angiogenic drug, and temsirolimus, an mTOR inhibitor, have synergistic anti-cancer effects in preclinical models. We conducted a phase I study of the combination in patients with advanced cancers.. A "3 + 3" study design was used. During the escalation phase, lenalidomide (orally, days 1-21) and temsirolimus (intravenously, once a week) were given at the following respective doses: level 1 (10 mg, 15 mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). The maximum tolerated dose, dose-limiting toxicity, and response were assessed.. Forty-three patients were treated (median age: 58 years (range, 21-80); male/female: 26/17). The most common diagnoses were colorectal cancer (N = 5), sarcoma (N = 5), neuroendocrine carcinoma (N = 4) and adenoid cystic carcinoma (N = 4). Overall, 121 cycles (median: 2) were administered. No dose-limiting toxicities were observed. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related hematologic toxicities (all reversible) were seen in 19 (72%) patients and included neutropenia (N = 12), thrombocytopenia (N = 6), and infection (N = 1). Grade 3 hyperglycemia and Grade 3 hypertriglyceridemia were noted in 21% and 20% of patients, respectively. Of 43 patients, 30 (70%) received prophylactic anticoagulation. There were no thrombotic events. Response was evaluable in 40 patients: one (2.5%) patient had a partial response and 19 (48%) had stable disease (SD), with SD ≥ 6 months in 6 (15%) patients. Tumor types with SD ≥ 6 months were soft tissue sarcoma (2/5; 40%), adenoid cystic carcinoma (1/4; 25%), parotid adenocarcinoma (1/2; 50%), adrenocortical carcinoma (1/3; 33%), and neuroendocrine carcinoma (1/4; 25%). The median progression-free survival duration was 2.2 months (95% CI, 1.5-2.9), and the median overall survival duration was 7.8 months (95% CI, 5.1-10.6).. Lenalidomide and temsirolimus combination therapy was well tolerated and associated with clinical benefit in patients with soft tissue sarcoma, adenoid cystic carcinoma, neuroendocrine carcinoma, parotid carcinoma, and adrenocortical carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Lenalidomide; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Sirolimus; Thalidomide; TOR Serine-Threonine Kinases; Young Adult

The mammalian target of rapamycin (mTOR) pathway is deregulated in castration-resistant prostate cancer (CRPC). We investigated the efficacy and toxicity of temsirolimus, an mTOR inhibitor, in chemotherapy-naïve CRPC.. In this phase II open label study, eligible patients received IV temsirolimus at 25 mg weekly until objective disease progression, unacceptable toxicity or investigator's discretion. Toxicity was assessed every 4 weeks and responses every 8 weeks. Primary end point was calculating the overall response (OR) rate as well as measuring stable disease (SD) to assess the overall clinical benefit calculated as OR+SD. Secondary end points included prostatic-specific antigen (PSA) changes and time to progression biochemically and radiographically. Correlative studies included prospective assessment of quality of life (QoL) using two previously validated scales.. Although the sponsor halted the study early, 21 patients were enrolled of which, 15 were evaluable for efficacy and OR. Median age was 74 (range: 57-89), median PSA was 237.5 ng ml(-1) (range: 8.2-2360), visceral disease present in 11 patients (52%), and 17 patients (81%) patients had Gleason score (7-10). Two patients had a partial response (PR) and eight had SD. The OR was 13% (2/15) and the overall clinical benefit (OR+SD) was 67% (10/15). Median time to radiographic disease progression was 2 months (range 2-10 months). Biochemical response assessment was available for 14/15 patients. Any PSA decline was observed in four patients (28.5%; 4/14) with one patient (7%) having >50% PSA decline. Median time to progression by PSA was 2 months (range 1-10 months). With a median follow-up of 32 months, median overall survival (OS) was 13 months (range: 2-37) and three patients remain alive at the data cutoff (5/2013) for an OS of 14% at 4 years on an intent-to-treat analysis. Major non-haematologic toxicities included fatigue (19%) and pneumonia (14%). Main laboratory toxicities included hyperglycaemia (24%) and hypophosphatemia (14%). Also, 52% of enrolled patients had serious adverse events. Other toxicities were consistent with previously reported adverse events with temsirolimus. Despite these observed adverse events, temsirolimus did not adversely impact QoL.. Temsirolimus monotherapy has minimal activity in chemotherapy-naïve CRPC.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Humans; Male; Middle Aged; Orchiectomy; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Kinase Inhibitors; Quality of Life; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients.. This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor-positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events).. Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003).. Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Humans; Letrozole; Middle Aged; Neoplasm Metastasis; Nitriles; Placebos; Postmenopause; Sirolimus; Treatment Outcome; Triazoles

This two-stage phase II study was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma (EMC).. Eligible patients had persistent or recurrent EMC after receiving 1-2 prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status ≤ 2. Treatment consisted of bevacizumab 10 mg/kg every other week and temsirolimus 25 mg IV weekly until disease progression or prohibitory toxicity. Primary end points were progression-free survival (PFS) at six months and overall response rate using RECIST criteria.. Fifty-three patients were enrolled. Forty-nine patients were eligible and evaluable. Median age was 63 years, and prior treatment consisted of one or two regimens in 40 (82%) and 9 (18%), respectively. Twenty (41%) received prior radiation. Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment. Two gastrointestinal-vaginal fistulas, one grade 3 epistaxis, two intestinal perforations and 1 grade 4 thrombosis/embolism were seen. Three patient deaths were possibly treatment related. Twelve patients (24.5%) experienced clinical responses (one complete and 11 partial responses), and 23 patients (46.9%) survived progression free for at least six months. Median progression-free survival (PFS) and overall survival (OS) were 5.6 and 16.9 months, respectively.. Combination of temsirolimus and bevacizumab is deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC. However, this treatment regimen was associated with significant toxicity in this pretreated group. Future study will be guided by strategies to decrease toxicity and increase response rates.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Disease-Free Survival; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Sirolimus

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Diphenhydramine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Eruptions; Early Termination of Clinical Trials; Fatigue; Female; Hematologic Diseases; Histone Deacetylase Inhibitors; Humans; Infusions, Intravenous; Male; Mucositis; Neoplasms; Pain; Sirolimus; Valproic Acid

There are few effective therapies for high-risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mammalian target of rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose-finding portion of this study. Adult and pediatric patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose-limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m(2) monthly with temsirolimus 20 mg/m(2) weekly. Hematologic toxicity was common but manageable. Dose-limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Co-administration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Child; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Male; Middle Aged; Recurrence; Sarcoma; Sirolimus; Young Adult

The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy.. Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines.. Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression.. The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Class I Phosphatidylinositol 3-Kinases; Cyclin-Dependent Kinase Inhibitor p16; Cytokines; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Platinum; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Quinazolines; Ribosomal Protein S6 Kinases; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

The purpose of this phase I trial was to establish the maximum tolerated dose and define the dose-limiting toxicities of a combination of temsirolimus and metformin. Patients with advanced solid tumours who had exhausted standard treatment options were eligible. Treatment included weekly intravenous temsirolimus and daily oral metformin. Eleven patients were enrolled. Dose-limiting toxicities were observed in all patients at the initial dose level of 25 mg weekly of temsirolimus and metformin 500 mg po BID. At dose level -1, 2 of 8 patients experienced dose-limiting toxicities. Toxicities included grade 4 pneumonitis, persistent grade 3 fatigue, and thrombocytopenia requiring dose delays. The maximum tolerated dose (level -1) was 20 mg temsirolimus weekly and 500 mg po daily of metformin. One patient with head and neck cancer experienced a partial response. Five patients had stable disease including a patient with melanoma who had stable disease for 22 months.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Metformin; Middle Aged; Neoplasms; Ontario; Pilot Projects; Protein Kinase Inhibitors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

The purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin-paclitaxel (Taxol)-temsirolimus.. Patients with solid malignancies suitable for carboplatin-paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration.. Days 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n=2) and grade 3 fatigue (n=1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs.. Carboplatin-paclitaxel-temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m2, both given on day 1 with temsirolimus 25 mg on days 1 and 8.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Paclitaxel; Sirolimus

Purpose Activation of EGFR can stimulate proliferative and survival signaling through mTOR. Preclinical data demonstrates synergistic activity of combined EGFR and mTOR inhibition. We undertook a phase I trial of temsirolimus (T, an mTOR inhibitor) and EKB-569 (E, an EGFR inhibitor) to determine the safety and tolerability. Methods The primary aim was to determine the maximally tolerated dose (MTD) of this combination in adults with solid tumors. Following the dose-escalation phase, (Cohort A), two subsequent cohorts were used to assess any pharmacokinetic (PK) interaction between the agents. Results Forty eight patients were enrolled. The MTD of this combination was E, 35 mg daily and T, 30 mg on days 1-3 and 15-17 using a 28-day cycle. The most common toxicities were nausea, diarrhea, fatigue, anorexia, stomatitis, rash, anemia, neutropenia, thrombocytopenia, and hypertriglyceridemia. Sixteen patients (36%) had at least one grade 3 toxicity. The most frequent grade 3/4 toxicities were diarrhea, dehydration, and nausea and vomiting (19% each). No grade 5 events were seen. Four patients had a partial response and 15 had stable disease. Clinical benefit was seen across a range of tumor types and in all cohorts. PK analysis revealed no significant interaction between E and T. Conclusions This combination of agents is associated with tolerable toxicities at doses that induced responses. PK studies revealed no interaction between the drugs. Further investigations of this targeting strategy may be attractive in renal cell carcinoma, non-small cell lung cancer, alveolar sarcoma, and carcinoid tumor.

Topics: Adult; Aged; Aged, 80 and over; Aminoquinolines; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; ErbB Receptors; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

A phase II study of temsirolimus was conducted in children and adolescents with high-grade glioma, neuroblastoma or rhabdomyosarcoma.. Temsirolimus 75 mg/m(2) was administered once weekly until disease progression or intolerance. Using the Simon 2-stage design, further enrolment in each disease cohort required ≥ 2 objective responses within the first 12 weeks for the first 12 evaluable patients (those who received ≥ 3 temsirolimus doses).. Fifty-two heavily pretreated patients with relapsed (12%) or refractory (88%) disease, median age 8 years (range 1-21 years), were enroled and treated. One patient with neuroblastoma achieved confirmed partial response within the first 12 weeks; thus, none of the 3 cohorts met the criterion for continued enrolment. Disease stabilisation at week 12 was observed in 7 of 17 patients (41%) with high-grade glioma (5 diffuse pontine gliomas, 1 glioblastoma multiforme and 1 anaplastic astrocytoma), 6 of 19 (32%) with neuroblastoma and 1 of 16 (6%) with rhabdomyosarcoma (partial response confirmed at week 18). In the three cohorts, median duration of stable disease or better was 128, 663 and 75 d, respectively. The most common treatment-related adverse events were thrombocytopaenia, hyperlipidaemia and aesthenia. Pharmacokinetic findings were similar to those observed in adults.. Temsirolimus administered weekly at the dose of 75 mg/m(2) did not meet the primary objective efficacy threshold in children with high-grade glioma, neuroblastoma or rhabdomyosarcoma; however, meaningful prolonged stable disease merits further evaluation in combination therapy.

Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Cohort Studies; Disease Progression; Female; Glioma; Humans; Infusions, Intravenous; Male; Neuroblastoma; Rhabdomyosarcoma; Sirolimus

The mammalian target of rapamycin (mTOR) signalling pathway has emerged as an important therapeutic target for acute myeloid leukaemia (AML). This study assessed the combination of temsirolimus, an mTOR inhibitor, and lower-dose clofarabine as salvage therapy in older patients with AML. Induction consisted of clofarabine 20mg/m(2) on days 1-5 and temsirolimus 25mg (flat dose) on days 1, 8 and 15. Patients achieving complete remission with (CR) or without (CRi) full haematological recovery could receive monthly temsirolimus maintenance. In 53 evaluable patients, the overall remission rate (ORR) was 21% (8% CR, 13% CRi). Median disease-free survival was 3·5months, and median overall survival was 4months (9·1months for responders). The most common non-haematological severe adverse events included infection (48%), febrile neutropenia (34%) and transaminitis (11%). The 30-d all-cause induction mortality was 13%. Laboratory data from 25 patients demonstrated that a >50%in vivo inhibition of S6 ribosomal protein phosphorylation was highly correlated with response rate (75% with inhibition versus 0% without inhibition; P=0·0001), suggesting that targeting the mTOR pathway is clinically relevant. The acceptable safety profile and the predictive value of target inhibition encourage further investigation of this novel regimen.

Topics: Adenine Nucleotides; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Clofarabine; Disease-Free Survival; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Salvage Therapy; Sirolimus; TOR Serine-Threonine Kinases

Topics: Adolescent; Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Child; Child, Preschool; Drug Synergism; Erlotinib Hydrochloride; Female; Humans; Indoles; Male; Molecular Targeted Therapy; Neurofibromatosis 2; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome; Valproic Acid; Vascular Endothelial Growth Factor A; Young Adult

This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma.. Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins.. A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK.. Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Female; Humans; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Proto-Oncogene Proteins B-raf; Pyridines; Sirolimus; Sorafenib; Survival Analysis; Treatment Outcome; Young Adult

Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma.. This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens.. On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR.. The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyridines; Quinolones; Sirolimus; Sorafenib; Survival Analysis; Treatment Outcome

Preclinical models suggested that activating mutations of the PIK3CA gene are associated with sensitivity to inhibitors of the mammalian target of rapamycin (mTOR). In breast cancers, PIK3CA mutations are associated with estrogen receptor (ER) positivity. We therefore performed an open-label single arm phase II study of the rapamycin analog, temsirolimus, at a dose of 25 mg weekly, in women with pretreated breast cancers that were positive for ER, PR, or HER2. Archived formalin-fixed paraffin embedded tumor was collected for immunohistochemical evaluation of components of the PI3K/Akt/mTOR pathway and PIK3CA mutation analysis. Thirty-one patients were enrolled. There were no major objective responses; however, three patients had stable disease for over 24 weeks. Twenty-three tumor samples were available for mutational analysis. There were five tumors with PIK3CA mutations; no association was found between prolonged stable disease and PIK3CA mutation or any immunohistochemical marker. There was a trend toward improved progression free survival (PFS) for patients with positive nuclear staining for phospho-Akt308. One patient remains on study four and a half years after starting therapy; her tumor did not have a PIK3CA mutation. We conclude that single agent temsirolimus has minimal activity in a population of women with heavily pretreated breast cancer. We found no evidence that either absence of immunohistochemical staining for PTEN or mutations in the hotspot domains of PIK3CA in the primary tumor were associated with clinical benefit.

Topics: Antineoplastic Agents; Breast Neoplasms; Disease Progression; Female; Humans; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

Temsirolimus, a selective inhibitor of mammalian target of rapamycin, is an approved treatment for patients with advanced renal cell carcinoma (RCC). This study assessed the effect of intravenous (i.v.) temsirolimus 25 mg, the recommended dose for patients with RCC, on the corrected QT (QTc) interval.. This 3-period crossover study enrolled healthy subjects. In periods 1 and 2, subjects received i.v. placebo either alone or with open-label oral moxifloxacin. In period 3, subjects received a single dose of temsirolimus 25 mg. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QTc at the end of infusion (0.5 h). Assay sensitivity was evaluated by the effect of moxifloxacin on change from time-matched baseline QTc compared with placebo.. In total, 58 subjects were enrolled. Temsirolimus had no effect on QTc interval in the primary analysis. At 11 of 12 secondary time points, the upper bound for the temsirolimus QTc 90% confidence intervals for the time-matched change from baseline difference from placebo was <10 ms, with no evidence of QTc trends or relationship to concentrations of temsirolimus or its major metabolite, sirolimus. Moxifloxacin, the positive control, produced a significant increase in the QTc interval compared with placebo 0.5-4 h post-dose (P < 0.0001). No subject had a QTc interval exceeding 450 ms or a change from baseline of >30 ms.. Therapeutic exposure to temsirolimus is not associated with clinically significant changes in QTc intervals in healthy adults.

Topics: Adolescent; Adult; Anti-Infective Agents; Antineoplastic Agents; Aza Compounds; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Electrocardiography; Female; Fluoroquinolones; Humans; Male; Middle Aged; Moxifloxacin; Placebos; Protein Kinase Inhibitors; Quinolines; Single-Blind Method; Sirolimus

This phase II trial assessed temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), as second-line therapy in patients with metastatic transitional carcinoma of the urothelium (TCCU) after failure of platinum containing therapy. From June/2009 to June/2011, we enrolled 15 patients in this trial. Primary endpoint was overall survival, as secondary endpoints we defined time to disease progression, safety and QoL along treatment. Patients with progressive TCCU after prior platinum-based chemotherapy received weekly 25 mg of temsirolimus for 8 weeks. Evaluation for response was accomplished every 8 weeks according to the RECIST criteria, QoL assessment was done every 4 weeks using the QLQ-C30 questionnaire, adverse events (AEs) were recorded and graded using NCI-CTC criteria. Fifteen patients were enrolled in this study, of whom 14 (93%) were available for activity, safety and QoL assessment. We treated 10 (71%) male and 4 female (29%) patients. Median age was 64,7 years (45-76). Patients received on average 13 (3-15) infusions of temsirolimus. As per protocol, no sufficient benefit on overall survival was observed, we early stopped the study after 14 patients. Median time to progression was 2.5 months (77 days), median overall survival was 3.5 months (107 days). Four patients with stable disease were observed. QoL assessment along treatment revealed a reduction of EORTC-QLQ-C30, Global Health Status subscale, from initial 7.86 to 5.00. Temsirolimus was well tolerated. As Grade 3-4 adverse events, we observed fatigue (n=2), leukopenia (n=2) and thrombopenia (n=2). All other adverse events were graded 1-2 in nature. Temsirolimus seems to have poor activity in patients with progressive metastasized TCCU after failure of platinum containing first-line therapy.

Topics: Aged; Antineoplastic Agents; Carcinoma, Transitional Cell; Female; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Quality of Life; Sirolimus; Urinary Bladder Neoplasms

Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R).. Patients received cixutumumab, 6 mg/kg i.v. weekly, and temsirolimus, 25 to 37.5 mg i.v. weekly (4-week cycles), with restaging after 8 weeks. Median follow-up was 8.9 months.. Twenty patients [17 with Ewing's sarcoma (EWS), 3 with desmoplastic small-round cell tumor (DSRCT)] were enrolled. Twelve patients (60%) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%; mostly grade I-II). Seven of 20 patients (35%) achieved stable disease (SD) for more than 5 months or complete/partial (CR/PR) responses. Tumor regression of more than 20% (23%, 23%, 27%, 100%, 100%) occurred in five of 17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six patients with EWS who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade III mucositis, myelosuppression, or hyperglycemia, which were controlled while maintaining drug dose.. Cixutumumab combined with temsirolimus was well-tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated EWS family tumors.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cohort Studies; Desmoplastic Small Round Cell Tumor; Female; Humans; Male; Neoplasm Grading; Prognosis; Receptor, IGF Type 1; Remission Induction; Sarcoma, Ewing; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

The mammalian target of rapamycin complex 1 (mTORC1) is aberrantly activated in many head and neck squamous cell carcinomas (HNSCCs). This phase I study combines the mTORC1 inhibitor temsirolimus with carboplatin and paclitaxel.. This was a single institution phase I study for patients with R/M HNSCC with a standard 3 + 3 design. Three doses of temsirolimus were planned: 15, 20, and 25 mg. Due to excessive toxicity with the original study regimen, the protocol was amended to carboplatin AUC 1.5, paclitaxel 80 mg/m(2), and temsirolimus (according to dose escalation plan), all on days 1 and 8 of a 21-day cycle.. 18 patients (14 male, 4 female) enrolled, with median age 56 years (range 33-78). The most common toxicities were anemia, leukopenia, thrombocytopenia, and hyperglycemia. Among all patients treated, the confirmed objective partial response (cPR) rate was 22 %. DLT was not exceeded among 6 patients treated at dose level 3 of the revised protocol, and 4 of 6 subjects treated at this dose level had cPRs.. The phase II recommended regimen is temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m(2), all on days 1 and 8 of a 21-day cycle. A phase II study of this regimen in R/M HNSCC is ongoing.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Hyperglycemia; Leukopenia; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Sirolimus; Thrombocytopenia; Treatment Outcome

In an effort to evaluate the single agent activity of temsirolimus in previously untreated non-small-cell lung cancer, the North Central Cancer Treatment Group undertook a frontline "window-of-opportunity" study.. Patients received 25 mg of temsirolimus administered intravenously as a weekly 30 minute infusion, on a 4-week cycle. Based on a two-stage Fleming design, the treatment would be promising if at least four of the first 25 evaluable patients in stage I or at least six of the 50 evaluable patients at the end of stage II have a confirmed response. Fresh tumor biopsies were obtained to evaluate predictive markers of temsirolimus activity.. A total of 55 patients were enrolled with 52 patients being evaluable. The median age was 64 years. Adverse events (grade 3/4) occurring in 33 patients included dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). The clinical benefit rate was 35% with four patients achieving a confirmed partial response and 14 patients with stable disease for 8 weeks or more. The 24-week progression-free survival rate was 25%. Median progression-free survival and overall survival were 2.3 and 6.6 months, respectively. Expression of p70s6 kinase, phospho-p70s6 kinase, Akt, phospho-Akt, and phosphatase and tensin homolog mutation did not correlate with clinical outcome.. Temsirolimus given as a single agent in frontline therapy in patients with non-small-cell lung cancer was tolerable and demonstrated clinical benefit but did not meet the primary objective in this study. Patient selection will be needed to enhance the efficacy.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Female; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Middle Aged; Phosphorylation; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Tumor Cells, Cultured

Temsirolimus, an inhibitor of the mammalian target of rapamycin, is approved for treatment of patients with advanced renal cell carcinoma in the USA and Europe. Temsirolimus was not yet evaluated in East Asian patients.. This non-randomized Phase II study enrolled 82 patients with advanced renal cell carcinoma [20 (24%) Japanese, 30 (37%) Korean and 32 (39%) Chinese patients; median age (range): 55 (26-83) years]. Most (71%) received prior systemic therapy for metastatic disease; two-thirds were intermediate risk. Six Japanese patients received intravenous temsirolimus 20 mg/m(2) weekly for tolerability assessment (Group A); the remaining 76 received a 25 mg flat dose weekly (Group B). Temsirolimus was dosed once weekly. Primary efficacy end point was the Response Evaluation Criteria in Solid Tumors-defined clinical benefit rate in the intent-to-treat population.. In the entire population, regardless of treatment group, the clinical benefit rate was 48% (95% confidence interval: 36, 59). Objective response rate was 11% (95% confidence interval: 5, 20), median progression-free survival was 7.3 months (95% confidence interval: 4.0, 9.2) and median time to treatment failure was 5.4 months (95% confidence interval: 3.5, 7.4). No patient in Group A demonstrated dose-limiting toxicity. The most frequent Grade 3 or 4 drug-related adverse events were anemia, hyperglycemia, hypophosphatemia and stomatitis (5% each). Serious adverse events reported in ≥ 5% of patients were pneumonia (9%) and interstitial lung disease (7%). Temsirolimus and its major metabolite, sirolimus, were long-lived throughout the dosage interval, with no evidence of accumulation.. Temsirolimus was well tolerated and showed promising activity in Japanese, Korean and Chinese patients with advanced renal cell carcinoma.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Asian People; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Hyperglycemia; Hypophosphatemia; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Outpatients; Protein Kinase Inhibitors; Sirolimus; Stomatitis; Treatment Outcome

Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines.. We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N = 136) were enrolled according to a modified 3 + 3 design plus dose expansion in responsive tumor types.. The most common cancers were breast (n = 29), epithelial ovarian (n = 23), and colorectal cancer (n = 17). The median number of prior chemotherapy regimens was four (range: 0-16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand-foot syndrome, hypertension, and fistula. This regimen led to a 21% (n = 28) stable disease (SD) ≥ 6 months and 21% (n = 29) rate of partial or complete remission [PR/CR; (total SD ≥ 6 months/PR/CR = 42% (n = 57)]. PR/CR was most common in parotid gland adenocarcinoma (4/6, 67%), metaplastic breast cancer (5/12, 42%), endometrial endometrioid carcinoma (6/15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11/28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m(2) and bevacizumab 15 mg/kg every three weeks with temsirolimus 25 mg weekly.. Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast, and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antibiotics, Antineoplastic; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Carcinoma, Ovarian Epithelial; Colorectal Neoplasms; Disease-Free Survival; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Protein Kinase Inhibitors; Sirolimus

The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Disease-Free Survival; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Niacinamide; Phenylurea Compounds; Sirolimus; Sorafenib; Young Adult

Carbonic anhydrase 9 (CA9) has been found to be one of most powerful biomarkers for clear-cell renal cell carcinoma (RCC). The serum CA9 is detectable. The aim of this study was to evaluate the potential prognostic role of serum CA9 in patients with metastatic clear-cell RCC patients under targeted therapy.. Serum samples came from the randomized phase 2 TORAVA trial. All patients received a targeted therapy (arm A designed as experimental group: temsirolimus and bevacizumab combination; arm B: sunitinib; arm C: interferon-alfa and bevacizumab). Seventy cases of metastatic clear-cell RCC were analyzed. There were 49 males and 21 females. The age ranged from 33.5 to 79.1 years with a median of 61.2 years. Serum samples were collected before treatment. Serum CA9 was quantified by enzyme-linked immunosorbent assay (ELISA). The correlation of the serum CA9 levels with the clinical parameters, treatment response and overall survival was analyzed. Overall survival estimates were calculated using the Kaplan-Meier method and compared by the log-rank test.. Serum concentrations of CA9 ranged between 0 and 897.3 pg/ml, with an average of 94.4±176.6 pg/ml. There was no association between serum CA9 and clinical parameters such as Eastern Cooperative Oncology Group (ECOG) Performance Status (p=0.367) or Motzer classification (p=0.431). The serum CA9 levels were lower in the response group (64.7±104.7 pg/ml) than the no-response group (108.2±203.8 pg/ml), but the difference was not statisticlly significant (p=0.366). For the patient group overall, the Kaplan-Meier survival curve showed that high serum CA9 levels were significantly associated with shorter overall survival (hazard ratio=2.65, 95% confidence interval=1.19-5.92, log-rank test p=0.0136). For the major group of patients treated with temsirolimus and bevacizumab, the Kaplan-Meier survival curve showed that high serum CA9 levels were significantly associated with shorter overall survival (p=0.0006).. Serum CA9 levels may be of clinical interest to predict the outcome for patients under targeted therapy for metastatic clear-cell RCC. CA9 may be used to select patients with metastatic clear cell RCC for clinical trials.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Carbonic Anhydrase IX; Carbonic Anhydrases; Carcinoma, Renal Cell; Enzyme-Linked Immunosorbent Assay; Female; Humans; Indoles; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Pyrroles; Sirolimus; Sunitinib; Treatment Outcome

Temsirolimus is an inhibitor of mammalian target of rapamycin, with proven efficacy against advanced renal cell carcinoma (RCC), particularly poor risk and/or non-clear cell RCC, in a randomized first-line phase III trial. In this trial, adverse events (AEs)≥grade 3 occurred in 47.6% of patients treated with temsirolimus alone (n＝208), and the common AEs included asthenia, anemia and hyperglycemia. During the observation period of this trial, drug-related pneumonitis was detected ; 4 patients developed temsirolimus-related pneumonitis, including 2 with ≥grade 3. To date, there have not been any reports analyzing data from a large number of Japanese RCC patients treated with temsirolimus. However, judging from our experience, the severity as well as the frequency of AEs associated with temsirolimus in Japanese patients seem to be similar to those in the Western population. In this study, we summarize our clinical experience with the use of temsirolimus focusing on its AEs and try to clarify the characteristics of temsirolimus-related AEs in Japanese patients, and then present our data relevant to this point from our clinical studies in order to discuss the significance of the management of AEs encountered during treatment with temsirolimus.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Pneumonia; Sirolimus

The primary goal of this trial was to evaluate the confirmed response rate of temsirolimus (CCI-779), a mammalian target of rapamycin in patients with advanced soft tissue sarcomas (STS).. Patients ≥18 years with measurable advanced STS, no prior chemotherapy for metastatic disease (adjuvant and neoadjuvant chemotherapy allowed), adequate organ function, and performance status of ≤2 were eligible. After premedication with an antihistamine, CCI-779 was given intravenously at 25 mg over 30 minutes on Days 1, 8, 15, and 22, repeated every 4 weeks. The primary endpoint was confirmed response rate per Response Evaluation Criteria in Solid Tumors.. Between June 2004 and November 2005, a total of 41 patients were enrolled and began treatment; 40 patients are evaluable for response and adverse events. The median age was 62 years (range, 28-72 years) with 56% women. Eighty percent had high-grade STS, and 22% had prior adjuvant chemotherapy. There were 2 patients (5%; 95% confidence interval [CI], 1-17) (undifferentiated fibrosarcoma and uterine leiomyosarcoma) who achieved a confirmed partial response lasting 3 and 17 months, respectively. Thirty-nine (95%) patients have progressed, with a median time to progression of 2.0 months (95% CI, 1.8-3.5). The median overall survival was 7.6 months (95% CI, 6.1-15.9). Forty-three percent experienced grade 3+ adverse events that were possibly related to therapy.. Temsirolimus in this patient population of STS had limited clinical activity and had moderate toxicities.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Sarcoma; Sirolimus

Multiple myeloma is the second most prevalent haematological malignancy and is incurable. Our aim was to assess the response and safety of the combination of temsirolimus (an mTOR inhibitor) and bortezomib in patients with relapsed or refractory multiple myeloma.. We did an open-label, dose-escalation study in three centres in the USA. Patients were enrolled from June, 2007, to December, 2009. Eligible patients were aged 18 years or older with relapsed or relapsed and refractory multiple myeloma after one or more treatment (including lenalidomide, bortezomib, or thalidomide), with an Eastern Cooperative Oncology Group performance status of 0-2. Patients were assigned a dose level in the order of their entry into the study. Phase 1 was to assess the safety and establish the maximum tolerated dose (MTD) of the combination and phase 2 was to assess overall response rate at the MTD. Intravenous temsirolimus was given at 15 or 25 mg and intravenous bortezomib at 1·3 or 1·6 mg/m(2) once a week, with dose escalation until dose-limiting adverse events were recorded in two of the three people in the dose cohort. Use of steroids were not permitted. The primary endpoint was the proportion of patients with a partial response or better. Analyses were done on an intention-to-treat basis, with all patients who had been enrolled included. The study is registered with ClinicalTrials.gov, number NCT00483262.. 20 patients were enrolled into the phase 1 study and 43 into phase 2. All patients were heavily pretreated (median five lines in the phase 1 cohort, and four lines in the phase 2 cohort). The MTD was determined to be 1·6 mg/m(2) bortezomib on days 1, 8, 15, and 22 in combination with 25 mg temsirolimus on days 1, 8, 15, 22, and 29, for a cycle of 35 days. In the phase 2 study, the proportion of patients with a partial response or better was 33% (14 of 43; 90% CI 21-47). Long-term follow-up of patients is ongoing. There were three deaths during treatment in the phase 1 and 2 studies: one patient died of septic shock in the phase 1 study; one patient died with H1N1 influenza infection and one died with cardiac amyloid and ventricular arrhythmia unrelated to treatment in the phase 2 study. In the phase 1 study, the most common treatment-related grade 3-4 adverse events were thrombocytopenia (13 patients), lymphopenia (ten), neutropenia (nine), leucopenia (seven), and anaemia (five). In the phase 2 study, the most common treatment-related grade 3-4 adverse events were thrombocytopenia (25 patients), lymphopenia (24), neutropenia (17), leucopenia (ten), anaemia (seven), and diarrhoea (five). Four patients in the phase 1 study had sensory peripheral neuropathy (grade 2 or less); in the phase 2 study, 11 had sensory peripheral neuropathy (all grade 2 or less) and seven motor peripheral neuropathy (one grade 3, six grade 2 or less).. mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids.. Millennium Inc, Pfizer Inc, Multiple Myeloma Research Foundation, and the Leukemia and Lymphoma Society.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Boronic Acids; Bortezomib; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Multiple Myeloma; Pyrazines; Recurrence; Sirolimus

Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor with single-agent antitumour activity in patients with mantle cell lymphoma. We therefore tested its efficacy and toxicity in combination with rituximab (an antiCD20 antibody) in patients with relapsed or refractory mantle cell lymphoma.. In a phase 2 study, patients (aged ≥18 years) at 35 centres in the USA were given temsirolimus 25 mg/week, and rituximab 375 mg/m(2) per week for 4 weeks during the first cycle and thereafter a single dose of rituximab every other 28-day cycle. Both drugs were administered intravenously. Responding patients after six cycles could continue treatment for a total of 12 cycles, and were then observed without additional maintenance treatment. The primary endpoint was the proportion of patients with either rituximab-sensitive or rituximab-refractory disease who had at least a partial response. The analyses were done on all patients who were treated. The study was registered with ClinicalTrials.gov, number NCT00109967.. 71 patients with mantle cell lymphoma were enrolled and 69 were assessable and were included in the final analysis. The overall response rate (ORR) was 59% (41 of 69 patients)-13 (19%) patients had complete responses and 28 (41%) had partial responses. The ORR was 63% (30 of 48; 95% CI 47-76) for rituximab-sensitive patients, and 52% (11 of 21; 30-74) for rituximab-refractory patients. The most common treatment-related grade 3 or 4 adverse events in rituximab-sensitive and rituximab-refractory patients were thrombocytopenia (eight [17%] and eight [38%], respectively), neutropenia (ten [21%] and five [24%], respectively), fatigue (eight [17%] and two [10%], respectively), leucopenia (six [13%] and three [14%], respectively), pneumonia (five [10%] and two [10%], respectively), lymphopenia (five [10%] and two [10%], respectively), pneumonitis (four [8%] and none, respectively), oedema (four [8%] and none, respectively), dyspnoea (three [6%] and two [10%], respectively), and hypertriglyceridaemia (three [6%] and two [10%], respectively).. mTOR inhibitors in combination with rituximab could have a role in the treatment of patients with relapsed and refractory mantle cell lymphoma.. National Institutes of Health and the Predolin Foundation.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Recurrence; Rituximab; Sirolimus

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Carcinoma; Doxorubicin; Female; Humans; Metaplasia; Middle Aged; Neoplasm Metastasis; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Sirolimus; Stem Cell Transplantation; Treatment Outcome

Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma.. TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov, number NCT00619268.. Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29.5% (26 of 88 patients, 95% CI 20.0-39.1) in group A, 35.7% (15 of 42, 21.2-50.2) in group B, and 61.0% (25 of 41, 46.0-75.9) in group C. Median PFS was 8.2 months (95% CI 7.0-9.6) in group A, 8.2 months (5.5-11.7) in group B, and 16.8 months (6.0-26.0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively.. The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma.. French Ministry of Health and Wyeth Pharmaceuticals.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indoles; Interferon-alpha; Male; Middle Aged; Neoplasm Staging; Pyrroles; Sirolimus; Sunitinib

To determine dose-limiting toxicities, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of weekly intravenous temsirolimus, a mammalian target of rapamycin (mTOR) signaling pathway inhibitor, in pediatric patients with recurrent or refractory solid tumors.. Cohorts of three to six patients 1 to 21 years of age with recurrent or refractory solid tumors were treated with a 1-hour intravenous infusion of temsirolimus weekly for 3 weeks per course at one of four dose levels: 10, 25, 75, or 150 mg/m(2). During the first two courses, pharmacokinetic and pharmacodynamic evaluations (phosphorylation of S6, AKT, and 4EBP1 in peripheral-blood mononuclear cells) were performed.. Dose-limiting toxicity (grade 3 anorexia) occurred in one of 18 evaluable patients at the 150 mg/m(2) level, which was determined to be tolerable, and an MTD was not identified. In 13 patients evaluable for response after two courses of therapy, one had complete response (CR; neuroblastoma) and five had stable disease (SD). Four patients (three SDs + one CR) remained on treatment for more than 4 months. The sum of temsirolimus and sirolimus areas under the concentration-time curve was comparable to values in adults. AKT and 4EBP1 phosphorylation were inhibited at all dose levels, particularly after two courses.. Weekly intravenous temsirolimus is well tolerated in children with recurrent solid tumors, demonstrates antitumor activity, has pharmacokinetics similar to those in adults, and inhibits the mTOR signaling pathway in peripheral-blood mononuclear cells. Further studies are needed to define the optimal dose for use in combination with other antineoplastic agents in pediatric patients.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Antineoplastic Agents; Cell Cycle Proteins; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Infusions, Intravenous; Male; Maximum Tolerated Dose; Neoplasms; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; United States; Young Adult

Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab.. Patients in sequential cohorts ("3 + 3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD).. Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3.. Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Middle Aged; Multimodal Imaging; Neoplasm Staging; Neoplasms; Positron-Emission Tomography; Protein Kinase Inhibitors; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers.. Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1-3 prior regimens were treated with 25mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendall's tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome.. Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90% CI 14.9%-38.6%) had PFS ≥6 months (median 3.1 months), 9.3% (90% CI 3.7%-23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic (8), gastrointestinal (8), pain (6), constitutional (5) and pulmonary (4). Suggested associations were between cyclin D1 and PFS ≥6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥6 months/longer PFS.. Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Cyclin D1; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasms, Glandular and Epithelial; Neoplastic Cells, Circulating; Ovarian Neoplasms; Peritoneal Neoplasms; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting.. Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles.. In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome.. mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Cohort Studies; Disease Progression; Endometrial Neoplasms; Female; Humans; Middle Aged; Mutation; Neoplasm Metastasis; Recurrence; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM.. A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions.. Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate.. The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.

Topics: Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Drug Interactions; Humans; Lenalidomide; Maximum Tolerated Dose; Multiple Myeloma; Neoplasm Recurrence, Local; Sirolimus; Survival Rate; Thalidomide; Tissue Distribution; Treatment Outcome

Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates.. Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immunhistochemistry for PTEN loss were conducted.. This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27-79); prior regimens: 4 (1-11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%).. DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Female; Genital Neoplasms, Female; Humans; Middle Aged; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; ras Proteins; Sirolimus; Survival Rate

An oral formulation of temsirolimus (Torisel), an inhibitor of the mammalian target of rapamycin, was evaluated on an intermittent schedule (once daily for 5 days every 2 weeks) in patients with advanced cancer. The maximum tolerated dose was determined to be 75 mg after dose-limiting toxicities of grade 3 elevated aminotransferases (1 patient) and grade 3 rash (1 patient) occurred with a 100-mg dose. The most common temsirolimus-related adverse events were mucositis, rash/maculopapular rash, and asthenia. Six of 12 patients who received the 75-mg dose required dose reductions due to temsirolimus-related adverse events. Two patients who received 75-mg temsirolimus and did not have dose reductions had minor tumor responses. Relative exposure from contributions of both temsirolimus and sirolimus, the principal metabolite, was 17.9% of the 75-mg dose. Thus, oral temsirolimus, 75 mg administered once daily for 5 days every 2 weeks, was further evaluated in patients with metastatic breast cancer.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Activation of the mammalian target of rapamycin (mTOR) pathway in surgical margins of head and neck squamous cell carcinoma (HNSCC) is a predictor of recurrence and patients with minimal residual disease may benefit from adjuvant therapy with temsirolimus, an mTOR inhibitor.. The effects of 3 weekly doses of 25 mg of temsirolimus on Akt/mTOR pathway biomarkers were evaluated in tumor and peripheral blood mononuclear cells (PBMCs) of patients with HNSCC. Adverse events were assessed.. Temsirolimus significantly decreased pS6 and p4E-BP1 in tumors, and pS6 and pAkt in PBMCs (p < .05). There was no significant upregulation of pAkt(Ser(473)) in tumor tissue. Side effects were minimal and reversible.. Significant inhibition of the mTOR pathway was noted in both tumors and PBMCs of HNSCC with minimal side effects. The mTOR inhibitors can potentially be used as adjuvant therapy for patients with minimal residual disease and PBMCs are potential surrogate markers in this setting.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

This report summarizes the U.S. Food and Drug Administration (FDA)'s approval of temsirolimus (Torisel), on May 30, 2007, for the treatment of advanced renal cell carcinoma (RCC). Information provided includes regulatory history, study design, study results, and literature review. A multicenter, three-arm, randomized, open-label study was conducted in previously untreated patients with poor-prognosis, advanced RCC. The study objectives were to compare overall survival (OS), progression-free survival (PFS), objective response rate, and safety in patients receiving interferon (IFN)-alpha versus those receiving temsirolimus alone or in combination with IFN-alpha. In the second planned interim analysis of the intent-to-treat population (n = 626), there was a statistically significant longer OS time in the temsirolimus (25 mg) arm than in the IFN-alpha arm (median, 10.9 months versus 7.3 months; hazard ratio [HR], 0.73; p = .0078). The combination of temsirolimus (15 mg) and IFN-alpha did not lead to a significant difference in OS compared with IFN-alpha alone. There was also a statistically significant longer PFS time for the temsirolimus (25 mg) arm than for the IFN-alpha arm (median, 5.5 months versus 3.1 months; HR, 0.66, p = .0001). Common adverse reactions reported in patients receiving temsirolimus were rash, asthenia, and mucositis. Common laboratory abnormalities were anemia, hyperglycemia, hyperlipidemia, and hypertriglyceridemia. Serious but rare cases of interstitial lung disease, bowel perforation, and acute renal failure were observed. Temsirolimus has demonstrated superiority in terms of OS and PFS over IFN-alpha and provides an additional treatment option for patients with advanced RCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Approval; Female; Humans; Immunologic Factors; Interferon-alpha; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Male; Middle Aged; Prognosis; Protein Serine-Threonine Kinases; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; United States; United States Food and Drug Administration; Young Adult

The mTOR inhibitor, temsirolimus, has clinical activity in the treatment of gynecologic malignancies, particularly endometrial cancer. We sought to determine the tolerability of the combination of weekly topotecan with weekly temsirolimus.. Women with a history of advanced or recurrent gynecologic malignancy refractory to curative therapy were enrolled. A starting dose of 1mg/m(2) of intravenous topotecan days 1, 8 and 15 was combined with 25mg temsirolimus days 1, 8, 15 and 22 of a 28 day cycle. Patients with and without prior pelvic radiotherapy (RT) were dose-escalated in separate cohorts.. Fifteen patients were treated on study. Forty-three cycles were administered, with between 1 and 7 cycles received per patient. Patient characteristics included ovarian cancer (n=7), endometrial cancer (n=3), uterine carcinosarcoma (n=3), and cervical cancer (n=2); performance status 0 (n=10) and 1 (n=5); prior chemotherapy regimens one (n=8), two (n=4), and three (n=3). Dose-limiting toxicity included asymptomatic neutropenia and thrombocytopenia. Four patients without prior pelvic RT were successfully treated with 1mg/m(2) topotecan with 25mg temsirolimus, days 1, 8, and 15 of a 28 day cycle. The combination was not tolerated in patients with a history of pelvic RT.. Dose-limiting toxicity for the combination of temsirolimus with topotecan was myelosuppression. The regimen may be safe in women who have not previously received radiation, but full doses of each agent could not be administered in combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genital Neoplasms, Female; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Recurrence, Local; Sirolimus; Topotecan

Temsirolimus (CCI-779) is a novel inhibitor of the mammalian target of rapamycin. This Phase 1 study was aimed at investigating the maximum-tolerated dose, toxicity, pharmacokinetics and antitumor activity in Japanese patients with advanced solid tumors.. Temsirolimus was given as a 30 min intravenous infusion once a week. Patients with solid tumors not amenable to standard forms of treatment were eligible. Dose escalation of temsirolimus was planned from 15, 45, 80 to 165 mg/m(2). The pharmacokinetics of temsirolimus and sirolimus in whole blood were examined for cycles 1, 2, 4 and 5 of treatment.. Ten patients (median age 60.5 years; range 41-69 years) with advanced solid tumors were enrolled. Their primary cancers were renal cell carcinoma (five patients), lung cancer (three patients) and colorectal cancer (two patients). The major toxicities were hypophosphatemia diarrhea, hyperglycemia, stomatitis, pyrexia, elevated aspartate aminotransferase, rash, reduced neutrophil count, elevated alanine aminotransferase, anorexia, hypertriglyceridemia and somnolence. Two of three patients who received temsirolimus 45 mg/m(2) developed dose-limiting toxicities of Grade 3 stomatitis (one patient) and Grade 3 diarrhea (two patients). The maximum-tolerated dose was 15 mg/m(2). The peak blood concentrations of temsirolimus and sirolimus, a major active metabolite, increased in a dose-dependent manner. The area under the concentration-versus-time curve of sirolimus, but not temsirolimus, increased in a dose-dependent manner.. The recommended dose for Phase 2 clinical studies of temsirolimus in Japanese patients with advanced solid tumors is 15 mg/m(2) intravenously once a week.

Topics: Adult; Aged; Anti-Allergic Agents; Antineoplastic Agents; Area Under Curve; Carcinoma, Renal Cell; Colorectal Neoplasms; Diarrhea; Diphenhydramine; Disorders of Excessive Somnolence; Drug Administration Schedule; Drug Eruptions; Fever; Humans; Hyperglycemia; Hypertriglyceridemia; Hypophosphatemia; Infusions, Intravenous; Intestinal Perforation; Kidney Neoplasms; Lung Neoplasms; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Premedication; Sirolimus; Stomatitis; Treatment Outcome

To compare long-interval T2-weighted subtraction (T2w-Sub) imaging with monthly gadolinium-enhanced T1-weighted (Gd-T1w) imaging for (1) detection of active lesions, (2) assessment of treatment efficacy, and (3) statistical power, in a multiple sclerosis (MS), phase 2, clinical trial setting.. Magnetic resonance imaging (MRI) data over 9 months from 120 patients (61 treatment, 59 placebo) from the oral temsirolimus trial were used. T2w-Sub images were scored for active lesions, independent of the original reading of the monthly Gd-T1w images. Treatment efficacy was evaluated using the nonparametric Mann-Whitney U test, and parametric negative binomial (NB)-regression and power calculations were conducted.. Datasets from 116 patients (58 treatment, 58 placebo) were evaluated. The mean number of T2w-Sub lesions in the treatment group was 3.0 (+/-4.6) versus 5.9 (+/-8.8) for placebo; the mean cumulative number of new Gd-T1w lesions in the treatment group was 5.5(+/-9.1) versus 9.1(+/-17.2) for placebo. T2w-Sub imaging showed increased power to assess treatment efficacy compared with Gd-T1w imaging, when evaluated by Mann-Whitney U test (p = 0.017 vs p = 0.177), or NB-regression without (p = 0.011 vs p = 0.092) or with baseline adjustment (p < 0.001 vs p = 0.002). Depending on the magnitude of the simulated treatment effect, sample size calculations showed reductions of 22 to 34% in the number of patients (translating into reductions of 81-83% in the number of MRI scans) needed to detect a significant treatment effect in favor of T2w-Sub imaging.. Compared with monthly Gd-T1w imaging, long-interval T2w-Sub MRI exhibited increased power to assess treatment efficacy, and could greatly increase the cost-effectiveness of phase 2 MS trials by limiting the number of patients, contrast injections, and MRI scans needed.

Topics: Adult; Brain; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gadolinium; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Outcome Assessment, Health Care; Protein Kinase Inhibitors; Sirolimus; Statistics, Nonparametric

Temsirolimus was approved in Europe as first-line treatment of poor-prognosis advanced renal cell carcinoma (advRCC) based on significant clinical benefits.. Patients with advRCC and multiple poor-prognostic factors were randomly assigned to receive 25 mg intravenous temsirolimus weekly, interferon-alpha (titrated to 18 mU) three times weekly, or 15 mg intravenous temsirolimus weekly plus 6 mU of interferon-alpha three times weekly. EuroQol-5D utility score (EQ-5D index) and the EQ-5D visual analogue scale (EQ-VAS) responses were recorded. For analysis, patients were required to have their EQ-5D data recorded at baseline, week 12, and last visit after week 12. The analysis was conducted using last-visit data and a repeated-measures mixed-effect (RMME) model to evaluate quality-of-life differences between temsirolimus and interferon-alpha, controlling for baseline covariates.. Average EQ-5D score at the last measure was significantly higher in patients receiving temsirolimus compared with interferon-alpha: by 0.10 on EQ-5D index (P=0.0279) and by 6.61 on EQ-VAS (P=0.0095). In the RMME model, the least-square mean for on-treatment EQ-5D index score was 0.590 with temsirolimus and 0.492 with interferon-alpha (P=0.0022).. Temsirolimus is associated with significantly higher EQ-5D scores compared with interferon-alpha in patients with previously untreated poor-prognosis advRCC.

Topics: Activities of Daily Living; Antineoplastic Agents; Carcinoma, Renal Cell; Health Status; Humans; Interferon-gamma; Kidney Neoplasms; Quality of Life; Sirolimus

For patients with advanced cancers, it is important that treatment improves the quality as well as the quantity of survival. This quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) analysis provides a combined measure of both the overall survival interval and the quality of survival for patients with advanced renal cell carcinoma (RCC) receiving temsirolimus, interferon (IFN)-alpha or the combination of these agents, using data from a phase III clinical trial.. Overall survival was partitioned into three distinct health states: time with serious toxicity (TOX), time after progression (REL) and time without symptoms of progression or toxicity (TWiST). Health states were quality weighted by patient-reported EQ-5D measures collected while receiving treatment.. All 626 patients from the trial were included in computation of health-state durations. EQ-5D questionnaires were obtained from 260 patients upon progression and from 230 after a grade 3 or 4 adverse event, and from 278 patients in the TWiST state. Patients receiving temsirolimus had 38% longer TWiST than those receiving IFNalpha (6.5 vs 4.7 months, respectively; p = 0.0005). Patients receiving temsirolimus had 25% longer quality-adjusted survival in terms of Q-TWiST than those receiving IFNalpha (7.0 vs 5.6 months, respectively; p = 0.0015). Differences between the combination (temsirolimus + IFNalpha) and IFNalpha groups were not statistically significant. Threshold utility analysis indicated that temsirolimus was the preferred alternative for all possible utility weights for REL and TOX health states.. Temsirolimus resulted in significantly longer Q-TWiST (quality-adjusted survival) in patients with advanced RCC than IFNalpha therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Interferon Type I; Kidney Neoplasms; Male; Middle Aged; Quality-Adjusted Life Years; Recombinant Proteins; Sirolimus; Surveys and Questionnaires; Young Adult

The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR) kinase is an important mediator for its signaling. Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models.. Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN.. Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively). One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2). Grade 4 toxicity: hyponatremia (n = 1), Grade 3: diarrhea (n = 1), cholangitis (n = 3), hyperglycemia (n = 1), fatigue (n = 1). Grade 2: pneumonia (n = 2), dehydration (n = 2), nausea (n = 2), neutropenia (n = 1), mucositis (n = 2) & rash (n = 2). Four patients were hospitalized. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed a higher pAkt/Akt ratio in tumor specimens that in nonmalignant pancreatic tissue. No such trends were noted for the other biomarkers.. Neither study with mTOR inhibitors demonstrated objective responses or disease stability. The negative feedback loop resulting from mTOR inhibition may account for the disease progression and toxicity noted in these studies. Future strategies should aim for a broader targeting of the PI3K pathway in pancreatic cancer.. NCT 0075647.. NCT00640978.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; ErbB Receptors; Erlotinib Hydrochloride; Everolimus; Female; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Phosphorylation; Prognosis; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinazolines; Signal Transduction; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases

Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas.. We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas).. Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis.. Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Marrow; Chicago; Disease-Free Survival; Female; Humans; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Mucositis; Pneumonia; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Remission Induction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival.. The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy.. Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells.. The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed.

Topics: Aged; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Protein Kinase Inhibitors; Risk Factors; Sirolimus; Treatment Outcome

Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin (mTOR), is approved for treatment of renal cell carcinoma. In vitro studies with pooled human liver microsomes showed that temsirolimus and its principal metabolite, sirolimus, inhibit the CYP2D6 isozyme (K(i) = 1.5 and 5 microM, respectively), indicating potential for pharmacokinetic interaction with agents that are substrates of CYP2D6.. This 2-period study in healthy subjects investigated the pharmacokinetics of a single oral 50-mg dose of the CYP2D6 substrate desipramine, first without and subsequently with a single coadministered i.v. 25-mg dose of temsirolimus.. The study population consisted of 25 males and 1 female; 10 were black, 12 were white, and 4 were of other races. Plasma and whole blood samples were available from all 26 subjects in period 1 following oral desipramine and from 23 subjects in period 2 following oral desipramine and i.v. temsirolimus coadministration. The 90% confidence intervals for least squares geometric mean ratios of desipramine and 2-hydroxy-desipramine C(max), AUC(T), and AUC were within 80-125%, indicating that parameter differences did not manifest into clinically relevant exposure changes. A single i.v. 25-mg dose of temsirolimus, alone or with desipramine, was well tolerated in healthy subjects.. A single i.v. 25-mg dose of temsirolimus did not alter disposition of desipramine. Temsirolimus i.v. 25 mg may be safely administered with agents metabolized through the CYP2D6 pathway, but vigilance for drug interaction is warranted in patients with advanced malignancies.

Topics: Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Area Under Curve; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Desipramine; Drug Combinations; Drug Interactions; Enzyme Inhibitors; Female; Humans; Injections, Intravenous; Male; Middle Aged; Sirolimus; Substrate Specificity; Young Adult

Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC.. Eligibility included advanced RCC and or= 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/microL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/microL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents.. Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cellulitis; Diarrhea; Drug Eruptions; Female; Humans; Indoles; Infusions, Intravenous; Kidney Neoplasms; Male; Middle Aged; Pyrroles; Sirolimus; Stomatitis; Sunitinib; Thrombocytopenia; Treatment Outcome

Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with temsirolimus (Torisel) or interferon-alpha (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Sirolimus; Treatment Outcome

In a phase II trial, 16 patients with relapsed refractory multiple myeloma received temsirolimus 25mg I.V. weekly until progression. One partial response and 5 minor responses were observed for a total response rate of 38%. The median time to progression was 138 days. Grade 3-4 toxicity included fatigue (n=3), neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), stomatitis (n=1) and diarrhea (n=1). Clinical activity was associated with a higher area under the curve (AUC) and maximal reduction in phosphorylated p70(S6)K and 4EBP1 in peripheral blood mononuclear cells. At the dose and schedule used, temsirolimus had low single agent activity. Investigation of alternate dosing schedules and use in combinations is indicated.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Multiple Myeloma; Recurrence; Sirolimus

Positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models.. Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1.. Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression.. FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.

Topics: Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Proliferation; Disease Progression; Female; Fluorodeoxyglucose F18; Glucose Transporter Type 1; Humans; Mice; Mice, Nude; Neoplasms; Patient Selection; Phosphorylation; Positron-Emission Tomography; Predictive Value of Tests; Protein Kinases; Proto-Oncogene Proteins c-akt; Radiopharmaceuticals; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome; Xenograft Model Antitumor Assays

Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 alpha correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon-alpha (IFN).. Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 alpha baseline levels were measured in archived tumor specimens by immunohistochemistry.. There was no correlation between baseline PTEN and HIF1 alpha levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors.. The baseline status of the molecular markers PTEN and HIF1 alpha did not correlate with efficacy in renal cell carcinoma patients treated with temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with temsirolimus regardless of PTEN and HIF1 alpha status. Thus, baseline PTEN and HIF-1 levels may not predict response to temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to temsirolimus in patients with advanced renal cell carcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; PTEN Phosphohydrolase; Signal Transduction; Sirolimus

Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease.. In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment.. Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia.. Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Protein Kinase Inhibitors; Protein Kinases; Recurrence; Sirolimus; TOR Serine-Threonine Kinases

Intravenous temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved for the treatment of advanced renal cell carcinoma (RCC). Sirolimus, the principal metabolite of temsirolimus in humans, also exhibits mTOR inhibitory activity.. The purpose of this study was to compare the pharmacokinetics of temsirolimus and its metabolite, sirolimus, among patients with RCC not receiving dialysis and those receiving hemodialysis.. This was a single-center, unblinded, single-dose study. Patients with histologically confirmed metastatic RCC were eligible. A single 25-mg dose of temsirolimus was administered as a 30-minute intravenous infusion during the first round of chemotherapy. Blood samples were drawn at 0 (predose), 0.5 (end of infusion), 1.5, 2.5, 5.5, 24, 72, and 144 hours after infusion. In patients receiving hemodialysis, an additional blood sample was drawn 1 hour after each treatment to compare pre- and postconcentration. Temsirolimus concentrations were assayed in blood using HPLC coupled to mass spectrometry. Pharmacokinetic parameters (C(max), T(max), t((1/2)), AUC(0-infinity), total body clearance, volume of distribution at steady state, AUC ratio [the ratio of sirolimus to temsirolimus AUCs], and AUC sum [the algebraic sum of temsirolimus and sirolimus AUCs]) were calculated and analyzed statistically.. In total, 13 consecutive patients (11 men and 2 women; 11 not receiving dialysis and 2 receiving hemodialysis) were included. No patient refused to participate in the study. Of those not receiving dialysis, the median age was 54 years (range, 36-77 years), and of those receiving hemodialysis, the median age was 60.5 years (60-61 years). There were no significant between-group differences in the pharmacokinetic parameters of temsirolimus and sirolimus. Moreover, in patients receiving hemodialysis, blood drug concentrations assessed immediately before hemodialysis were similar to those assayed 1 hour after the treatment.. This study found that after single-dose administration of 25 mg of temsirolimus as a 30-minute intravenous infusion, neither temsirolimus nor sirolimus concentrations were significantly affected in these patients with RCC receiving hemodi-alysis compared with those not receiving dialysis.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Carcinoma, Renal Cell; Chromatography, High Pressure Liquid; Female; Half-Life; Humans; Kidney Neoplasms; Male; Mass Spectrometry; Middle Aged; Renal Dialysis; Sirolimus; Tissue Distribution

The objective of this study was to test a low dose of (25 mg weekly) of the mammalian target of rapamycin kinase inhibitor temsirolimus for patients with relapsed mantle cell lymphoma (MCL).. Patients with relapsed or refractory MCL were eligible to receive temsirolimus 25 mg intravenously every week as a single agent. Patients who had a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission and then were observed without maintenance.. Of 29 enrolled patients, 28 were evaluable for toxicity, and 27 were evaluable for efficacy. The median age was 69 years (range, 51-85 years), 86% of patients had stage IV disease, and 71% had > or = 2 extranodal sites. Patients had received a median of 4 prior therapies (range, 1-9 prior therapies), and 50% were refractory to the last treatment. The overall confirmed response rate was 41% (11 of 27 patients; 90% confidence interval [CI], 22%-61%) with 1 complete response (3.7%) and 10 partial responses (37%). The median time to progression in all eligible patients was 6 months (95% CI, 3-11 months), and the median duration of response for the 11 responders was 6 months (range, 1-26 months). Hematologic toxicities were the most common, with 50% (14 of 28 patients) grade 3 and 4% (1 of 28 patients) grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reduction.. Single-agent temsirolimus at a dose of 25 mg weekly is an effective new agent for the treatment of MCL. The 25-mg dose level retained the antitumor activity of the 250-mg dose with less myelosuppression. Further studies of temsirolimus in combination with other active drugs for MCL and other lymphoid malignancies are warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Recurrence; Sirolimus; Survival Analysis; Treatment Outcome; United States

Temsirolimus, a novel inhibitor of mammalian target of rapamycin, has demonstrated prolonged overall survival and progression-free survival compared with interferon alfa (IFN) in patients with advanced renal cell carcinoma (RCC) and poor prognostic features. Adverse events (AEs) of any causality were previously reported, but AEs that were deemed temsirolimus related are of particular relevance for poor-risk patients and for defining mammalian target of rapamycin inhibitor-specific side-effects.. Patients with advanced RCC, no prior systemic therapy, and three or more of six poor-risk factors were randomly assigned to one of three groups: (i) IFN s.c. up to 18 MU thrice weekly, (ii) temsirolimus i.v. 25 mg weekly, or (iii) temsirolimus i.v. 15 mg weekly plus interferon s.c. 6 MU thrice weekly.. Among 208 patients, the most common temsirolimus-related grades 3-4 AEs were anemia (13%), hyperglycemia (9%), and asthenia (8%). Grades 3-4 hypercholesterolemia (1%), hypertriglyceridemia (3%), and hypophosphatemia (4%) were also seen. Although pneumonitis occurred infrequently, vigilance for its development is needed. Guidelines for management of toxic effects are presented on the basis of available clinical experience.. Temsirolimus-related grades 3-4 AEs were primarily metabolic in nature and easily controlled medically. In general, these did not negatively impact patient quality of life.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Sirolimus

Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.. In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.. Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).. As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Hematologic Diseases; Humans; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Prognosis; Proportional Hazards Models; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases

Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC.. Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information.. Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months.. The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carcinoma, Renal Cell; Digestive System Diseases; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Hypersensitivity; Exanthema; Female; Humans; Interferon-alpha; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Respiratory Tract Diseases; Sirolimus

Temsirolimus is a novel inhibitor of the mammalian target of rapamycin, with antitumor activity in advanced tumors. Because temsirolimus and its metabolite, sirolimus, are cytochrome P450 (CYP) 3A4/5 substrates, the potential exists for interaction with drugs that induce CYP3A activity, including enzyme inducers and rifampin. Cancer patients received once-weekly intravenous (IV) 220 mg/m(2) temsirolimus with or without enzyme inducers. Coadministration with enzyme inducers decreased temsirolimus maximum plasma concentration (C(max)) by 36% and increased volume of distribution by 99%. Sirolimus C(max) and area under the concentration-time curve (AUC) were decreased by 67% and 43%, respectively. In healthy adult subjects, coadministration of 25-mg intravenous temsirolimus with rifampin had no significant effect on temsirolimus C(max) and AUC but decreased sirolimus C(max) and AUC by 65% and 56%, respectively. Rifampin decreased AUC(sum) by 41%. Temsirolimus was well tolerated in both studies. If concomitant agents with CYP3A induction potential are used, higher temsirolimus doses may be needed to achieve adequate tumor tissue drug levels.

Topics: Adolescent; Adult; Aged; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Enzyme Induction; Female; Glioma; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Protein Kinases; Rifampin; Sirolimus; TOR Serine-Threonine Kinases

To study the progression-free survival (PFS) and toxicity with 25- or 250-mg doses of temsirolimus (CCI-779) after induction chemotherapy in patients with extensive small-cell lung cancer.. Patients with either stable or responding disease to four to six cycles of cisplatin or carboplatin plus etoposide or irinotecan were randomized between 4 and 8 weeks after completion of induction therapy to receive either 25 or 250 mg of temsirolimus intravenously every week until disease progression.. Eighty-seven patients entered between January 2002 and December 2003, of whom 85 were eligible: 44 received 25 mg (arm A), and 41 received 250 mg (arm B). The overall median follow-up time for all eligible patients was 34.6 months. Median age was 59 years (range, 39-80); 42 (49.4%) were male and 43 (50.6%) female; 12.9% had brain metastases. The overall median and 1-year PFS were 2.2 months (95% confidence interval [CI]: 1.8, 2.9) and 4.7% (95% CI: 0.2%, 9.2%), respectively. The median PFS (95% CI) for arm A was 1.9 months (1.6, 2.3); for arm B, it was 2.5 months (1.9, 3.4; p = 0.24). The median overall survival from randomization was 8 months (95% CI: 6.5, 9.5). Among the 86 patients with reported toxicities, 36 (42%) had grade 3 toxicities, the most common of which were thrombocytopenia, hypophosphatemia, and fatigue, and an additional 12 (14%) had grade 4 toxicities, the most common of which was neutropenia. No patients experienced lethal toxicities.. Temsirolimus (CCI 779), given at 25 or 250 mg weekly, seemed not to increase the PFS in this patient population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Cisplatin; Etoposide; Female; Follow-Up Studies; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Protein Kinase Inhibitors; Remission Induction; Sirolimus; Survival Rate; Treatment Outcome

To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue.. Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis.. Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus.. Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.

Topics: Anticonvulsants; Antineoplastic Agents; Area Under Curve; Brain Neoplasms; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Glioma; Humans; Maximum Tolerated Dose; Metabolic Clearance Rate; Neoplasm Recurrence, Local; Sirolimus

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma; Costs and Cost Analysis; Double-Blind Method; Humans; Indoles; Interferon alpha-2; Interferon-alpha; Kidney Neoplasms; Pyrroles; Recombinant Proteins; Sirolimus; Sunitinib; Survival Analysis; Vascular Endothelial Growth Factor A

Patients with advanced cancer received temsirolimus (Torisel, CCI-779), a novel inhibitor of mammalian target of rapamycin, i.v. once daily for 5 days every 2 weeks to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and preliminary antitumor efficacy.. Doses were escalated in successive cohorts of patients using a conventional phase I clinical trial design. Samples of whole blood and plasma were collected to determine the pharmacokinetics of temsirolimus and sirolimus, its principal metabolite.. Sixty-three patients were treated with temsirolimus (0.75-24 mg/m(2)/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m(2)/d for patients with extensive prior treatment because, in the 19 mg/m(2)/d cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24 mg/m(2)/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m(2)/d as the maximum acceptable dose. Immunologic studies did not show any consistent trend toward immunosuppression. Temsirolimus exposure increased with dose in a less than proportional manner. Terminal half-life was 13 to 25 hours. Sirolimus-to-temsirolimus exposure ratios were 0.6 to 1.8. A patient with non-small cell lung cancer achieved a confirmed partial response, which lasted for 12.7 months. Three patients had unconfirmed partial responses; two patients had stable disease for >/=24 weeks.. Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Sirolimus

Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoid Tumor; Carcinoma, Neuroendocrine; Disease Progression; Exanthema; Fatigue; Female; Follow-Up Studies; Humans; Hyperglycemia; Infusions, Intravenous; Male; Middle Aged; Pancreatic Neoplasms; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome

Our objective was to estimate the pharmacokinetic parameters of CCI-779 and its metabolite, sirolimus, and evaluate associations of exposure parameters with safety and clinical activity. Exposure parameters were also correlated with pharmacogenomic responses in peripheral blood mononuclear cells (PBMCs).. In this randomized, double-blind, multicenter trial, once-weekly intravenous doses of 25, 75, or 250 mg CCI-779 were administered to patients with advanced renal cancer. Whole blood for CCI-779 and sirolimus concentrations was drawn. Population pharmacokinetic analyses yielded Bayesian-predicted exposure metrics that were correlated with severity and duration of adverse events and survival. PBMC samples taken before and after treatment were examined for pharmacogenomic responses. Ribonucleic acid samples were converted to labeled probes and hybridized to oligonucleotide arrays containing more than 12,600 human sequences.. The final population pharmacokinetic models of CCI-779 and sirolimus included 235 and 305 observations, respectively, from 50 patients. For CCI-779, dose, single versus multiple dose, and body surface area were significant pharmacokinetic covariates. For sirolimus, dose and hematocrit were significant covariates. Age, sex, or race did not influence drug disposition. CCI-779 area under the curve correlated with adverse event severity for thrombocytopenia (P = .007), pruritus (P = .011), and hyperlipemia (P = .040). Exposure (CCI-779 cumulative area under the curve) correlated with a specific subset of gene transcripts in PBMCs following 16 weeks after therapy (P < .001, Spearman correlation).. Concentrations of CCI-779 and sirolimus were adequately described with a population model incorporating factors for dose, attenuated exposure of multiple doses, body surface area, and hematocrit. Correlations with adverse event severity and duration profiles were provided to aid in the detection of treatment-emergent effects. Pharmacogenomic profiling of PBMCs identified altered ribonucleic acid transcript expression levels that correlate with exposure. These transcripts represent potential biomarkers of CCI-779 exposure in peripheral blood.

Topics: Adult; Aged; Area Under Curve; Double-Blind Method; Female; Humans; Kidney Neoplasms; Leukocytes, Mononuclear; Male; Metabolic Clearance Rate; Middle Aged; Pharmacogenetics; Severity of Illness Index; Sirolimus; Thrombocytopenia

In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated.. Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus.. Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%).. In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Bone Neoplasms; Breast Neoplasms; Female; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Protein Kinases; Safety; Salvage Therapy; Sirolimus; Soft Tissue Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM).. Recurrent GBM patients with < or = 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly.. Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04).. Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus-treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Disease-Free Survival; Female; Genes, erbB-1; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Phosphoric Monoester Hydrolases; Prognosis; Protein Kinase Inhibitors; Protein Kinases; PTEN Phosphohydrolase; Salvage Therapy; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Suppressor Proteins

CCI-779 is an analog of the immunosuppressive agent, rapamycin, that has demonstrated activity against melanoma in preclinical models and shown clinical benefit in patients with breast and renal carcinoma. CCI-779 is not immunosuppressive when administered on an intermittent schedule, and its toxicity is modest, consisting of nausea, diarrhea, hypertriglyceridemia, thrombocytopenia, asthenia, and follicular dermatitis.. The current trial was designed to detect a median time to disease progression of >18 weeks in patients with metastatic melanoma treated with a 250-mg weekly dose of CCI-779 administered intravenously after diphenhydramine premedication. Patients with measurable disease, no more than one previous chemotherapy regimen for metastatic disease, and normal organ function were eligible, and patients with central nervous system involvement, P450-inducing or P450-suppressing drugs, or hypertriglyceridemia were excluded.. Thirty-three patients (21 males) were treated, 21 of whom had been treated previously with chemotherapy and/or biologic agents for advanced-stage disease. One patient had a partial response lasting 2 months. The median time to disease progression and overall survival were 10 weeks and 5 months, respectively. Toxicity was mild and predominantly mucocutaneous (stomatitis, diarrhea, and rash). Hyperlipidemia was cumulative and was managed with lipid-lowering agents.. CCI-779 was not sufficiently active in melanoma to warrant further testing as a single agent.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Male; Melanoma; Middle Aged; Sirolimus

Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug.. CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival.. Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks.. CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.

Topics: Adult; Aged; Anemia; Anticonvulsants; Antineoplastic Agents; Brain Neoplasms; Disease-Free Survival; Drug Interactions; Female; Glioblastoma; Humans; Hypercholesterolemia; Infusions, Intravenous; Lymphopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Sirolimus

To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC).. Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics.. CCI-779 produced an objective response rate of 7% (one complete response and seven partial responses) and minor responses in 26% of these advanced RCC patients. Median time to tumor progression was 5.8 months and median survival was 15.0 months. The most frequently occurring CCI-779-related adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level. Patients were retrospectively classified into good-, intermediate-, or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa. Within each risk group, the median survivals of patients at each dose level were similar.. In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.

Topics: Aged; Aged, 80 and over; Biological Availability; Carcinoma, Renal Cell; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Kidney Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Probability; Prognosis; Risk Assessment; Salvage Therapy; Sirolimus; Survival Analysis; Treatment Outcome

To establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of the mammalian target of rapamycin, in patients with advanced cancer.. Using a modified continuous reassessment method, we performed a phase I with pharmacokinetic study of CCI-779 given as a weekly 30 minutes intravenous (I.V.) infusion.. Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m(2). No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m(2). At 220 mg/m(2), dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment discontinuation. Maximum concentration and area under the concentration-time curve increase sub-proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was nonlinear, ranging from 19 to 51 L/h (34 to 220 mg/m(2)). Variability predicted with flat doses appears comparable with data based on body-surface area-normalized treatment. Partial responses were observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma.. CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m(2), the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II trials in patients with breast and renal cancer.

Topics: Adult; Antineoplastic Agents; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Immunity; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; Skin; TOR Serine-Threonine Kinases

CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs.. The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria.. Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs.. The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

Topics: Adult; Anticonvulsants; Antineoplastic Agents; Brain Neoplasms; Cohort Studies; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Enzyme Induction; Female; Glioma; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Sirolimus; Treatment Outcome

CCI-779 is a novel ester of the immunosuppressive agent sirolimus that exerts cytostatic effects by the inhibition of the translation of cell-cycle regulatory proteins. We investigated the maximum tolerated dose (MTD) and pharmacokinetics (PK) of CCI-779 in combination with leucovorin (LV) and 5-fluorouracil (5-FU) in patients with advanced solid tumors.. Patients were treated with LV at 200 mg/m(2) as a 1-h i.v. infusion directly followed by continuous 24-h i.v. infusion of 5-FU, in the first patient at 2000 mg/m(2) and in subsequent patients at 2600 mg/m(2). CCI-779 was administered directly prior to LV as a 30-min i.v. infusion at a starting dose of 15 mg/m(2) beginning at day 8 and escalated in subsequent cohorts of patients. One cycle consisted of six weekly administrations followed by 1 week of rest. Blood samples were drawn to assess PK of CCI-779 as well as its effect on steady-state 5-FU exposures.. Twenty-eight patients entered the study, the majority having tumor types for which 5-FU is used as a treatment. CCI-779 doses of 15, 25, 45 and 75 mg/m(2) were investigated. Skin toxicity (rash) was prominent at all dose levels examined. Stomatitis was the dose-limiting toxicity (DLT) for 75 mg/m(2) doses of CCI-779. Subsequently the cohort at 45 mg/m(2) was expanded to a total of 15 patients, and at this dose level two treatment-related deaths occurred due to mucositis with bowel perforation. Based on the toxicities observed, it was decided to discontinue the study. Partial responses were observed in three patients with gastrointestinal tumors. No pharmacokinetic interaction between CCI-779 and 5-FU was observed.. The safety profiles of CCI-779 and 5-FU/LV suggest an overlap of drug-related toxicities, and the administration of these drugs at these doses and schedule resulted in unacceptable toxicity and therefore cannot be recommended. If CCI-779 is to be used in combination with 5-FU/LV, other doses or schedules of administration will need to be explored.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Sirolimus

TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis. Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1. To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice. Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPV-negative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.

Topics: Animals; Autophagic Cell Death; Autophagy-Related Protein-1 Homolog; Cell Line, Tumor; Cell Proliferation; Cell Survival; Everolimus; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Intracellular Signaling Peptides and Proteins; Mice; MTOR Inhibitors; Mutation; Sirolimus; Squamous Cell Carcinoma of Head and Neck; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; ErbB Receptors; Female; Ferroptosis; Gene Expression Regulation, Neoplastic; Glycosylation; Humans; Middle Aged; N-Acetylgalactosaminyltransferases; Ovarian Neoplasms; Ovary; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation

Radio-resistance is a leading cause of nasopharyngeal carcinoma (NPC) treatment failure and identification of sensitising therapeutic targets is an unmet need to enhance clinical management. Given that the mammalian target of rapamycin (mTOR) signalling confers resistance to cancer therapy, we investigated whether mTOR contributes to radio-resistance in NPC and pharmacological inhibition of mTOR can overcome radio-resistance. We found that mTOR mRNA and protein levels, and phosphorylation of its downstream effector were increased in radio-resistant NPC compared with parental cells. mTOR inhibitor temsirolimus inhibits proliferation and induces apoptosis in a panel of NPC cell lines. Importantly, temsirolimus acts synergistically with radiation and is effective against radio-resistant cells. Using radio-resistant xenograft mouse model, we validated the efficacy of temsirolimus in preventing tumour formation and inhibiting tumour growth. Temsirolimus overcome radio-resistance in NPC via inhibiting mTOR signalling. Our work provides the pre-clinical evidence that the combination of radiation and mTOR inhibitor may be a therapeutic strategy in NPC. Our findings might accelerate the initiation of clinical trials on radio-resistant NPC patients using temsirolimus.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Humans; Mammals; Mice; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Neuroblastoma (NB) patients with MYCN amplification or overexpression respond poorly to current therapies and exhibit extremely poor clinical outcomes. PI3K-mTOR signaling-driven deregulation of protein synthesis is very common in NB and various other cancers that promote MYCN stabilization. In addition, both the MYCN and mTOR signaling axes can directly regulate a common translation pathway that leads to increased protein synthesis and cell proliferation. However, a strategy of concurrently targeting MYCN and mTOR signaling in NB remains unexplored. This study aimed to investigate the therapeutic potential of targeting dysregulated protein synthesis pathways by inhibiting the MYCN and mTOR pathways together in NB.. Using small molecule/pharmacologic approaches, we evaluated the effects of combined inhibition of MYCN transcription and mTOR signaling on NB cell growth/survival and associated molecular mechanism(s) in NB cell lines. We used two well-established BET (bromodomain extra-terminal) protein inhibitors (JQ1, OTX-015), and a clinically relevant mTOR inhibitor, temsirolimus, to target MYCN transcription and mTOR signaling, respectively. The single agent and combined efficacies of these inhibitors on NB cell growth, apoptosis, cell cycle and neurospheres were assessed using MTT, Annexin-V, propidium-iodide staining and sphere assays, respectively. Effects of inhibitors on global protein synthesis were quantified using a fluorescence-based (FamAzide)-based protein synthesis assay. Further, we investigated the specificities of these inhibitors in targeting the associated pathways/molecules using western blot analyses.. Co-treatment of JQ1 or OTX-015 with temsirolimus synergistically suppressed NB cell growth/survival by inducing G1 cell cycle arrest and apoptosis with greatest efficacy in MYCN-amplified NB cells. Mechanistically, the co-treatment of JQ1 or OTX-015 with temsirolimus significantly downregulated the expression levels of phosphorylated 4EBP1/p70-S6K/eIF4E (mTOR components) and BRD4 (BET protein)/MYCN proteins. Further, this combination significantly inhibited global protein synthesis, compared to single agents. Our findings also demonstrated that both JQ1 and temsirolimus chemosensitized NB cells when tested in combination with cisplatin chemotherapy.. Together, our findings demonstrate synergistic efficacy of JQ1 or OTX-015 and temsirolimus against MYCN-driven NB, by dual-inhibition of MYCN (targeting transcription) and mTOR (targeting translation). Additional preclinical evaluation is warranted to determine the clinical utility of targeted therapy for high-risk NB patients.

Topics: Acetanilides; Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Apoptosis; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Down-Regulation; Drug Synergism; Eukaryotic Initiation Factor-4E; G1 Phase Cell Cycle Checkpoints; Heterocyclic Compounds, 3-Ring; Humans; N-Myc Proto-Oncogene Protein; Neuroblastoma; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Spheroids, Cellular; TOR Serine-Threonine Kinases; Transcription Factors; Triazoles

Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Drug Resistance, Neoplasm; Female; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred BALB C; Mice, SCID; Mutation; Neoplasm Transplantation; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Tumor Burden; Xenograft Model Antitumor Assays

The aim of this study was to evaluate the association between axitinib, sunitinib and temsirolimus toxicities and patient survival in metastatic renal cell cancer patients. Overall survival (OS) and progression-free survival (PFS) of metastatic renal cell cancer patients from the prospective multicenter STAR-TOR study were assessed using multivariable Cox models. A total of 1195 patients were included (n = 149 axitinib; n = 546 sunitinib; n = 500 temsirolimus). The following toxicities significantly predicted outcomes: hand-foot skin reaction (hazard ratio [HR] = 0.29) for PFS with axitinib; stomatitis (HR = 0.62) and pneumonitis (HR = 0.23) for PFS with temsirolimus; stomatitis (HR = 0.52) and thrombocytopenia (HR = 0.6) for OS with temsirolimus; fatigue (HR = 0.71) for PFS with sunitinib; hand-foot skin reaction (HR = 0.56) and fatigue (HR = 0.58) for OS with sunitinib. In conclusion, in metastatic renal cell cancer, axitinib, sunitinib and temsirolimus demonstrate specific toxicities that are protective OS/PFS predictors.

Topics: Aged; Axitinib; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Disease Progression; Fatigue; Female; Hand-Foot Syndrome; Humans; Incidence; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Pneumonia; Prognosis; Progression-Free Survival; Prospective Studies; Protective Factors; Risk Assessment; Sirolimus; Stomatitis; Sunitinib; Thrombocytopenia

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Humans; Infusions, Intra-Arterial; Male; Meningeal Neoplasms; Positron-Emission Tomography; Rhabdomyosarcoma; Sirolimus; Vinorelbine

Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P.. TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P.. Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53.. This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Clinical Trials, Phase II as Topic; Endometrial Neoplasms; Epothilones; Female; Genes, p53; Humans; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Progression-Free Survival; Randomized Controlled Trials as Topic; Sirolimus; Survival Rate; Treatment Outcome; Tumor Suppressor Protein p53

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Male; Prognosis; Prospective Studies; Registries; Risk Assessment; Sirolimus; Sunitinib; Survival Rate

Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chickens; Chorioallantoic Membrane; Drug Screening Assays, Antitumor; Drug Synergism; Glioblastoma; Humans; Neovascularization, Pathologic; Rats; Sirolimus; Tumor Cells, Cultured

We evaluated the radiosensitizing effect of the combination treatment of trametinib, a MEK inhibitor, and temsirolimus, an mTOR inhibitor, on non-small-cell lung carcinoma (NSCLC) cells.. The effects of combining trametinib and temsirolimus with radiation in NSCLC cell lines were evaluated using clonogenic survival and apoptosis assays. DNA double-strand breaks and cell cycle distribution were analyzed using flow cytometry. Tumor volume was measured to determine the radiosensitivity in lung cancer xenograft models.. The combination of trametinib and temsirolimus can enhance lung cancer radiosensitivity in vitro and in vivo.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; DNA Damage; Drug Therapy, Combination; Humans; Lung Neoplasms; MAP Kinase Kinase Kinases; Pyridones; Pyrimidinones; Radiation Tolerance; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

KRAS-mutant lung adenocarcinomas represent the largest molecular subgroup of non-small cell lung cancers (NSCLC) and are notorious for their dismal survival perspectives. To gain more insights in etiology and therapeutic response, we focused on the tumor suppressor Protein Phosphatase 2A (PP2A) as a player in KRAS oncogenic signaling. We report that the PP2A activator PTPA (encoded by PPP2R4) is commonly affected in NSCLC by heterozygous loss and low-frequent loss-of-function mutation, and this is specifically associated with poorer overall survival of KRAS-mutant lung adenocarcinoma patients. Reduced or mutant PPP2R4 expression in A549 cells increased anchorage-independent growth in vitro and xenograft growth in vivo, correlating with increased Ki67 and c-MYC expression. Moreover, KrasG12D-induced lung tumorigenesis was significantly accelerated in Ppp2r4 gene trapped mice as compared to Ppp2r4 wild-type. A confined kinase inhibitor screen revealed that PPP2R4-depletion induced resistance against selumetinib (MEK inhibitor), but unexpectedly sensitized cells for temsirolimus (mTOR inhibitor), in vitro and in vivo. Our findings underscore a clinically relevant role for PTPA loss-of-function in KRAS-mutant NSCLC etiology and kinase inhibitor response.

Topics: A549 Cells; Adenocarcinoma of Lung; Animals; Benzimidazoles; Cell Line, Tumor; Humans; Ki-67 Antigen; Mice; Mitogen-Activated Protein Kinase Kinases; Phosphoprotein Phosphatases; Protein Kinase Inhibitors; Protein Phosphatase 2; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Everolimus; Humans; Loss of Function Mutation; Melanoma; MTOR Inhibitors; Myeloid Cell Leukemia Sequence 1 Protein; Neurofibromin 1; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; Pyrimidines; Sirolimus; Sulfonamides; Thiophenes; Xenograft Model Antitumor Assays; Zebrafish

Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Glutamine; HCT116 Cells; HEK293 Cells; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Signal Transduction; Sirolimus; Xenograft Model Antitumor Assays

The phosphoinositide 3-kinase(PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway is hyperactivated in many tumors, as well as in cutaneous T-cell lymphoma (CTCL), which includes the mycosis fungoides and the aggressive variant known as Sezary syndrome (SS). TORC1 signaling is activated in SS cells by cytokines and chemokines, which are overexpressed in SS tissues. Furthermore, the recurrent copy number variation of genes belonging to this cascade, such as PTEN, LKB1, and P70S6K, contributes to the hyperactivation of the pathway. The aim of this study was to investigate the therapeutic potential of mTOR inhibitors in CTCL. We compared the efficacy of three rapalogs (rapamycin, temsirolimus, and everolimus) and the dual-mTOR/PI3K inhibitor PF-04691502 (hereinafter PF-502) in four CTCL cell lines. PF-502 was revealed to be the most effective inhibitor of cell growth. Interestingly, PF-502 also exerted its antitumor activity in patient-derived CTCL cells and in a xenograft mouse model, where it induced significant apoptosis and increased survival of treated mice. Furthermore, we found an inverse correlation between PTEN gene expression and the ability of PF-502 to induce apoptosis in SS cells. Our data strongly support the therapeutic potential of dual PI3K/mTOR inhibitors in CTCL.

Topics: Animals; Antineoplastic Agents; Cell Line; Drug Evaluation, Preclinical; Everolimus; Female; Humans; Lymphoma, T-Cell, Cutaneous; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Nude; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Signal Transduction; Sirolimus; T-Lymphocytes; Xenograft Model Antitumor Assays

Although the polymeric vascular disrupting agent (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4) nanoparticles (CA4-NPs) has great potential to inhibit cancer growth, it is still a challenge to avert tumor recurrence and metastasis after treatment. It is mainly tightly associated with hypoxia induced by CA4-NPs, which can activate many downstream genes regulating tumor growth and metastasis. Herein, to relieve a tumor hypoxia microenvironment, the mTOR inhibitor temsirolimus was employed to modulate the tumor microenvironment when treated with CA4-NPs. In vitro MTT experiments strongly verified that the combination of temsirolimus with polymeric CA4-NPs exhibited an additive toxicity to 4T1 cells. An in vivo study with the 4T1 mammary adenocarcinoma model revealed that consistent with the proposed scenario, combination therapy with CA4-NPs plus temsirolimus suppressed tumor growth significantly more strongly compared to either CA4-NPs or temsirolimus monotherapy, and the inhibition rate to 4T1 tumor with a volume of 300 mm

Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasm Metastasis; Neoplasms; Polyethylene Glycols; Polyglutamic Acid; Polymers; Sirolimus; Stilbenes; Tumor Microenvironment

Renal cell carcinoma (RCC) is a major cancer of the kidney. The 5-year survival rate is overall 74% and only 8% for Stage 4 cancers. Several agents including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors are available as first- or second-line therapy for metastatic RCC. However, the survival benefits are limited. Recently, THZ1 has been identified as a cyclin-dependent kinase 7 (CDK7) inhibitor that interferes with the transcriptional machinery. Although it is apparently effective in various cancer models, the data for RCC has never been reported. In this study, we demonstrated the impact of CDK7 expression on tumor progression and patient survival in a clinical cohort. We found that THZ1 induced apoptosis and cell cycle arrest in RCC cells, thereby reducing cell viability. Furthermore, THZ1 acted synergistically with temsirolimus in vitro, probably by inhibiting autophagy. Moreover, compared to either THZ1 or temsirolimus used individually, the combination treatment further suppressed tumor growth in vivo. These results indicate that CDK7 is associated with the progression and prognosis of RCC, and is a potential therapeutic target for overcoming drug resistance in this cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Carcinoma, Renal Cell; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Drug Synergism; Humans; Kidney Neoplasms; Mice; Mice, Nude; Neoplasm Staging; Phenylenediamines; Pyrimidines; Random Allocation; Sirolimus; Xenograft Model Antitumor Assays

We intended to design G250 antigen-targeting temsirolimus-loaded nanobubbles (G250-TNBs) based on the targeted drug delivery system and to combine G250-TNBs with ultrasound targeted nanobubble destruction (UTND) to achieve a synergistic treatment for renal cell carcinoma (RCC).. The filming-rehydration method was combined with mechanical shock and electrostatic interactions to prepare temsirolimus-loaded nanobubbles (TNBs). G250-TNBs were prepared by attaching anti-G250 nanobodies to the surface of TNBs using the biotin-streptavidin-bridge method. The ability of G250-TNBs to target the G250 antigen of RCC cells and the synergistic efficacy of G250-TNBs and UTND in the treatment of RCC were assessed.. The average diameter of the prepared G250-TNBs was 368.7 ± 43.4 nm, the encapsulation efficiency was 68.59% ± 5.43%, and the loading efficiency was 5.23% ± 0.91%. In vitro experiments showed that the affinity of G250-TNBs to the human RCC 786-O cells was significantly higher than that of TNBs (P <0.05), and the inhibitory effect on 786-O cell proliferation and the induction of 786-O cell apoptosis was significantly enhanced in the group treated with G250-TNBs and UTND (G250-TNBs+ UTND group) compared with the other groups (P <0.05). In a nude mouse xenograft model, compared with TNBs, G250-TNBs could target the transplanted tumors and thus significantly enhance the ultrasound imaging of the tumors. Compared with all other groups, the G250-TNBs+UTND group exhibited a significantly lower tumor volume, a higher tumor growth inhibition rate, and a higher apoptosis index (P <0.05).. The combined G250-TNBs and UTND treatment can deliver anti-tumor drugs to local areas of RCC, increase the local effective drug concentration, and enhance anti-tumor efficacy, thus providing a potential novel method for targeted therapy of RCC.

Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Humans; Kidney Neoplasms; Mice, Nude; Nanostructures; Sirolimus; Ultrasonography, Interventional; Xenograft Model Antitumor Assays

Lung cancer is the most common malignancy world-wide. Small cell lung cancer is the deadliest subtype of lung cancer, which features such as rapid growth, early metastasis, and high vascularization. Apatinib is a vascular endothelial growth factor receptor 2 inhibitor independently developed in China, which has a significant inhibition in a variety of solid tumors. The purpose of this study is to investigate the effects of Apatinib alone or Apatinib combined with mammalian target of rapamycin (mTOR) inhibitor, CCI-779, on small cell lung cancer cell line NCI-H446 in vitro.. The small cell lung cancer cell line NCI-H446 was grew in vitro. The effects of Apatinib alone or Apatinib combined with CCI-779 on proliferation, apoptosis, cell cycle and migration of NCI-H446 small cell lung cancer cells were detected by CCK8; FACS and transwell assays were also carried out; Western blot assays were used to detect vascular endothelial growth factor and cell cycle related protein expression.. CCK8 assays showed that high concentration of Apatinib could inhibit the proliferation of NCI-H446 cells. Apoptosis assays showed that high concentration of Apatinib could induce NCI-H446 cell apoptosis. Transwell assays showed that high concentration of Apatinib could inhibit NCI-H446 cell migration. After combined with mTOR inhibitor CCI-779, low concentration of Apatinib could inhibit the proliferation and migration of NCI-H446 small cell lung cancer cells and induce apoptosis.. Apatinib has a concentration-dependent effect on the small cell lung cancer cell line NCI-H446. High concentration of Apatinib can inhibit the proliferation and migration of NCI-H446 small cell lung cancer cells, induce apoptosis. Apatinib combined with the mTOR inhibitor CCI-779 can sensitize the NCI-H446 cells to Apatinib.. 【中文题目：阿帕替尼联合CCI-779体外抑制小细胞肺癌细胞株NCI-H446的增殖和迁移】 【中文摘要：背景与目的 肺癌是世界上最常见的恶性肿瘤，其中小细胞肺癌是恶性程度最高的亚型，具有生长迅速、早期转移和高度血管化等特点。阿帕替尼（Apatinib）是我国自主研发的血管内皮生长因子受体2抑制剂，在多种实体瘤中疗效显著。本研究旨在探讨Apatinib对小细胞肺癌细胞株NCI-H446的体外作用以及联合哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）抑制剂CCI-779对小细胞肺癌的体外作用。方法 体外培养小细胞肺癌细胞株NCI-H446，CCK8法、细胞凋亡实验、细胞周期实验及Transwell实验检测Apatinib及联合mTOR抑制剂CCI-779对NCI-H446细胞增殖、凋亡、周期及迁移的影响；Western blot实验检测血管内皮生长因子受体和细胞周期相关蛋白的表达。结果 CCK8实验结果显示高浓度Apatinib能抑制NCI-H446细胞增殖；细胞凋亡实验结果显示高浓度Apatinib诱导NCI-H446细胞凋亡；Transwell实验结果显示高浓度Apatinib抑制NCI-H446细胞迁移；联合mTOR抑制剂CCI-779后，低浓度Apatinib便能抑制NCI-H446细胞增殖和迁移，诱导细胞凋亡。结论 Apatinib对小细胞肺癌细胞株NCI-H446的作用具有浓度依赖性特征，高浓度Apatinib能够抑制NCI-H446细胞增殖和迁移，诱导细胞凋亡，与mTOR抑制剂CCI-779联用能增加NCI-H446细胞对Apatinib的敏感性。】 【中文关键词：肺肿瘤；阿帕替尼；mTOR抑制剂；CCI-779；细胞周期；凋亡；细胞迁移】.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Drug Interactions; Humans; Lung Neoplasms; Pyridines; Sirolimus; Small Cell Lung Carcinoma

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor including vascular endothelial growth factor, has been widely used as a first-line treatment against metastatic renal cell carcinoma (mRCC). However, mRCC often acquires resistance to sunitinib, rendering it difficult to treat with this agent. Recently, Rapalink-1, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink-1 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin. In comparison with temsirolimus, Rapalink-1 showed significantly greater effects against proliferation, migration, invasion and cFolony formation in sunitinib-naïve RCC cells. Inhibition was achieved through suppression of the phosphorylation of substrates in the mTOR signal pathway, such as p70S6K, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and AKT. In addition, Rapalink-1 had greater tumor suppressive effects than temsirolimus against the sunitinib-resistant 786-o cell line (SU-R 786-o), which we had previously established, as well as 3 additional SU-R cell lines established here. RNA sequencing showed that Rapalink-1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option for patients with RCC that is either sunitinib-sensitive or sunitinib-resistant.

Topics: Animals; Apoptosis; Carcinoma, Renal Cell; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Kidney Neoplasms; Mice; Mice, Nude; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Mechanistic Target of Rapamycin Complex 1; Meningeal Neoplasms; Meningioma; Mice; Mice, Nude; Mutation; Neoplasm Transplantation; Prolyl Hydroxylases; Protein Kinase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA-Seq; Signal Transduction; Sirolimus; Skull Base Neoplasms; Tumor Hypoxia; Up-Regulation

Treatment with molecular targeted agents together with immune checkpoint inhibitors will most likely improve the efficacy of current cancer immunotherapy. Because molecular targeted agents not only directly affect cancer cells, but also influence immune cells and modulate the tumor microenvironment, a better understanding of the overall immunological effects of these drugs will contribute to the rational design of combination therapies. Therefore, this study performed extensive immune monitoring of patients' peripheral blood mononuclear cells (PBMCs) to investigate the immunological effects of the molecular targeted agents sunitinib, everolimus and temsirolimus, which have been widely used for the treatment of renal cell carcinoma (RCC). Immunophenotyping and functional analysis of PBMCs revealed that these molecular targeted agents exerted different immunological effects on patients with RCC. Sunitinib decreased the percentage of early‑stage myeloid‑derived suppressor cells (eMDSCs) and increased natural killer cells, but did not affect the phenotypes and effector functions of CD4+ or CD8+ T cells. Everolimus decreased effector regulatory T cells, but also decreased IL‑2‑producing CD4+ T cells and increased dysfunctional CD8+ T cells. Conversely, temsirolimus decreased programmed cell death protein 1+CD8+ T cells and eMDSCs, but increased interferon‑γ and tumor necrosis factor‑α double producers at the same time as decreasing dysfunctional CD8+ T cells, albeit not significantly. In conclusion, although everolimus and temsirolimus are mTOR inhibitors, their effects on overall T‑cell functions are very different. Therefore, although it may increase the risk of immune‑related toxicity, temsirolimus is expected to offer the best outcome when combined with other immunomodulators for the development of cancer immunotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunotherapy; Kidney Neoplasms; Leukocytes, Mononuclear; Male; Middle Aged; Molecular Targeted Therapy; Programmed Cell Death 1 Receptor; Sirolimus; Sunitinib; T-Lymphocytes; Young Adult

Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.

Topics: Adult; Aged; Aged, 80 and over; Aging; Biomarkers; DNA Methylation; Epigenesis, Genetic; Epigenomics; Genomics; Humans; Male; Middle Aged; Mutation Rate; Organ Size; Precision Medicine; Prospective Studies; Prostate; Prostatic Hyperplasia; RNA-Seq; Signal Transduction; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome; Urological Agents; Whole Genome Sequencing

The identification of new targeted and personalized therapies for cancer requires the fast and accurate assessment of the drug efficacy of potential compounds against a particular biomolecular sample. It has been suggested that the integration of complementary sources of information might strengthen the accuracy of a drug efficacy prediction model. Here, we present a web-based platform for the Prediction of AntiCancer Compound sensitivity with Multimodal Attention-based Neural Networks (PaccMann). PaccMann is trained on public transcriptomic cell line profiles, compound structure information and drug sensitivity screenings, and outperforms state-of-the-art methods on anticancer drug sensitivity prediction. On the open-access web service (https://ibm.biz/paccmann-aas), users can select a known drug compound or design their own compound structure in an interactive editor, perform in-silico drug testing and investigate compound efficacy on publicly available or user-provided transcriptomic profiles. PaccMann leverages methods for model interpretability and outputs confidence scores as well as attention heatmaps that highlight the genes and chemical sub-structures that were more important to make a prediction, hence facilitating the understanding of the model's decision making and the involved biochemical processes. We hope to serve the community with a toolbox for fast and efficient validation in drug repositioning or lead compound identification regimes.

Topics: Antineoplastic Agents; Computer Simulation; Drug Repositioning; Gene Expression Profiling; Internet; Neural Networks, Computer; Sirolimus; Software

A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan.. Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30-60 minutes) in routine clinical settings (observation period: 96 weeks).. Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4-8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9-8.9) and 53.2% (95% confidence interval 49.3-57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9-21.1).. The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation. (ClinicalTrials.gov identifier NCT01210482, NCT01420601).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Japan; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Sirolimus; Treatment Outcome

EGFR inhibitors have shown poor efficacy in head and neck squamous cell carcinoma (HNSCC) with demonstrated involvement of the insulin-like growth factor-1 receptor (IGF1R) in resistance to EGFR inhibition. IGF1R activates the PI3K-Akt pathway, which phosphorylates proline-rich Akt substrate of 40 kDa (PRAS40) to cease mTOR inhibition resulting in increased mTOR signaling. Proliferation assays separated six HNSCC cell lines into two groups: sensitive to EGFR inhibition or resistant; all sensitive cell lines demonstrated reduced sensitivity to EGFR inhibition upon IGF1R activation. Reverse phase protein microarray analysis and immunoblot identified a correlation between increased PRAS40 phosphorylation and IGFR-mediated resistance to EGFR inhibition. In sensitive cell lines, PRAS40 phosphorylation decreased 44%-80% with EGFR inhibition and was restored to 98%-196% of control by IGF1R activation, while phosphorylation was unaffected in resistant cell lines. Possible involvement of mTOR in this resistance mechanism was demonstrated through a similar pattern of p70S6K phosphorylation. However, addition of temsirolimus, an mTORC1 inhibitor, was insufficient to overcome IGF1R-mediated resistance and suggested an alternative mechanism. Forkhead box O3a (FOXO3a), which has been reported to complex with PRAS40 in the cytoplasm, demonstrated a 6-fold increase in nuclear to cytoplasmic ratio upon EGFR inhibition that was eliminated with concurrent IGF1R activation. Transcription of FOXO3a-regulated TRAIL and PTEN-induced putative kinase-1 (PINK1) was increased with EGFR inhibition in sensitive cell lines; this effect was diminished with IGF1R stimulation. IMPLICATIONS: These data suggest PRAS40 may play an important role in IGF1R-based therapeutic resistance to EGFR inhibition, and this likely occurs via inhibition of FOXO3a-mediated proapoptotic gene transcription.

Topics: Adaptor Proteins, Signal Transducing; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Head and Neck Neoplasms; Humans; Insulin-Like Growth Factor I; Mechanistic Target of Rapamycin Complex 1; Phosphorylation; Protein Kinase Inhibitors; Receptor, IGF Type 1; Signal Transduction; Sirolimus; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases

Increased cytoplasmic lipid droplets (LDs) and elevated AKT/mTOR signaling are characteristics of clear cell renal cell carcinoma (ccRCC). Lysophosphatidic acid (LPA), a potent lipid mitogen generated via autotaxin (elevated in ccRCC), can modulate tumor progression but its role in altering chemotherapeutic sensitivity to mTOR inhibitors is unclear and thus is the focus of the studies presented herein. Using malignant (A-498, 769-P and 786-O) and normal immortalized kidney (HK-2) cell lines, we investigated their cellular responsiveness to Temsirolimus (TEMS, mTOR inhibitor) in the absence or presence of LPA by monitoring alterations in AKT/mTOR pathway mediators (via western blotting), LDs (using LipidTOX and real-time PCR to assess transcript changes in modulators of LD biogenesis/turnover), mitochondrial networks (via immunofluorescence staining for TOM20 and TOM70), as well as cellular viability. We identified that TEMS reduced cellular viability in all renal cell lines, with increased sensitivity in the presence of an autophagy inhibitor. TEMS also altered activation of AKT/mTOR pathway mediators, abundance of LDs, and fragmentation of mitochondrial networks. We observed that these effects were antagonized by LPA. In HK-2 cells, LPA markedly increased LD size and abundance, coinciding with phospho-MAPK and phospho-S6 activation, increased diacylglycerol O-acetyltransferase 2 (DGAT2) mRNA (which produces triacylglycerides), and survival. Inhibiting MAPK partially antagonized LPA-induced LD changes. Collectively, we have identified that LPA can reverse the effects of TEMS by increasing LDs in a MAPK-dependent manner; these results suggest that LPA may contribute to the pathogenesis and chemotherapeutic resistance of ccRCC.

Topics: Antineoplastic Agents; Autophagy; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Humans; Hydroxychloroquine; Kidney Neoplasms; Lipid Droplets; Lysophospholipids; Mitochondria; Phosphoric Diester Hydrolases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Chromosomal rearrangements are common in clear cell renal cell carcinoma (ccRCC) and their roles in mediating sensitivity to tyrosine kinase inhibitors (TKIs) and mTOR inhibitors (mTORi) remain elusive.. We developed an in silico strategy by screening copy number variance (CNV) that was potentially related to TKI or mTORi sensitivity in ccRCC by reproducing the TCGA and GDSC datasets. Candidate genes should be both significantly prognostic and related to drug sensitivity or resistance, and were then validated in vitro.. ADCYAP1 loss and GNAS gain were associated with sensitivity and resistance and to Cabozantinib, respectively. ACRBP gain and CTBP1 loss were associated with sensitivity and resistance and to Pazopanib, respectively. CDKN2A loss and SULT1A3 gain were associated with sensitivity and resistance and to Temsirolimus, respectively. CCNE1 gain was associated with resistance to Axitinib and LRP10 loss was associated with resistance to Sunitinib. Mutivariate analysis showed ADCYAP1, GNAS, and CCNE1 remained independently prognostic when adjusted for the rest.. Here we show CNVs of several genes that are associated with sensitivity and resistance to commonly used TKIs and mTORi in ccRCC. Further validation and functional analyses are therefore needed.

Topics: Anilides; Antineoplastic Agents; Arylsulfotransferase; Axitinib; Carcinoma, Renal Cell; Carrier Proteins; Cell Line, Tumor; Chromogranins; Computer Simulation; Cyclin E; DNA Copy Number Variations; Drug Resistance, Neoplasm; GTP-Binding Protein alpha Subunits, Gs; Humans; Indazoles; Kidney Neoplasms; Oncogene Proteins; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Eukaryotic translation initiation factor 4E (eIF4E) is deregulated in patients with renal cell carcinoma (RCC) and associated with poor prognosis, and is activated and regulated by Mnk kinases. In this study, we investigated the anti-RCC potential of a unique Mnk inhibitor cercosporamide. We showed that cercosporamide is active against RCC cells via suppressing growth, survival and migration. Combination indices value indicated that the combination of cercosporamide with sunitinib or temsirolimus are synergistic in RCC. In two independent RCC xenograft mouse models, complete tumor growth arrest or reverse was observed throughout the duration of drug treatment in the combination of cercosporamide with sunitinib or temsirolimus groups. Of note, cercosporamide inhibited RCC angiogenesis via negatively regulating a number of RCC endothelial cellular events including morphogenesis, migration, growth and survival. Mechanistically, we found that cercosporamide suppressed pro-angiogenic factors VEGF and HIFα, inhibited EMT and reduced pro-survival and cell cycle proteins; and furthermore this was attributed to cercosporamide's ability in inhibiting eIF4E. This work demonstrates the anti-RCC activity of cercosporamide through targeting both RCC tumor cells and angiogenesis, and provides the first preclinical proof-of-concept of evidence of Mnk inhibition for RCC treatment.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzofurans; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Synergism; Eukaryotic Initiation Factor-4E; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Mice, SCID; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

For metastatic renal cell carcinoma (RCC), various prognostic scoring systems have been developed. However, owing to the low prevalence of nonclear cell RCC, the three most commonly used tools were mainly developed based on patients with clear cell histology. Accordingly, this study applied three prognostic models to Korean non-clear cell RCC patients treated with first-line temsirolimus.. This study analyzed data for 74 patients with non-clear cell RCC who were treated with temsirolimus as the first-line therapy at eight medical centers between 2011 and 2016. The receiver-operating characteristic (ROC) curves for the different prognostic models were analyzed.. Twenty-seven (36.5%), 24 (32.4%), and 44 patients (59.5%) were assigned to the poor prognosis groups of the Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic RCC Database Consortium (IMDC), and Advanced Renal Cell Carcinoma (ARCC) risk stratification models, respectively. All three prognostic models reliably discriminated the risk groups to predict progression-free survival and overall survival (p < 0.001). The area under the ROC curve (AUC) for progression and survival was highest for the ARCC model (0.777; 0.734), followed by the IMDC (0.756; 0.724) and the MSKCC (0.742; 0.712) models. Furthermore, the sensitivity and specificity for predicting progression were highest with the ARCC model (sensitivity 63.6%, specificity 85.7%), followed by the MSKCC (sensitivity 58.2%, specificity 86.5%) and the IMDC models (sensitivity 56.4%, specificity 85.7%).. All three prognostic models accurately predicted the survival of the non-clear cell RCC patients treated with temsirolimus as the first-line therapy. Furthermore, the ARCC risk model performed better than the other risk models in predicting survival.

Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Prognosis; Retrospective Studies; Risk Assessment; Sirolimus

The mammalian target of rapamycin (mTOR) pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in MTOR, TSC1 and TSC2 was performed through targeted next-generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in MTOR, 1 in TSC1 and 2 in TSC2). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio [OR] = 0.08, 95% confidence interval [CI] = 0.008-0.79, p = 0.030 univariate; p = 0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR = 0.24, 95% CI = 0.065-0.86, p = 0.029 univariate; p = 0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR = 0.16, 95% CI = 0.04-0.62, p = 0.008 univariate; p = 0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC and their combination are potential markers of rapalog response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; DNA Mutational Analysis; Drug Resistance, Neoplasm; Everolimus; Female; Follow-Up Studies; Humans; Kidney; Kidney Neoplasms; Male; Middle Aged; Mutation; Prognosis; Progression-Free Survival; Prospective Studies; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein

The activity of MP1, a pyrrolomycin, was studied in MYCN amplified neuroblastoma (NB) alone and combined with temsirolimus (TEM).. Activity of MP1 was tested in MYCN amplified (BE-2c, IMR) and non amplified (SKN-AS) NB cells. The effect of MP1 on MYCN, MCL-1, cleaved PARP, LC3II/LC3I, bcl-2, BAX, and BRD-4 were determined by western blot and RNAseq. The effect of MP1 on metabolism, mitochondrial morphology, and cell cycle was determined. Toxicology and efficacy of MP1 plus TEM were evaluated.. The IC. MP1 has a potent inhibitory effect on the viability of MYCN amplified NB. Inhibition of metabolism by MP1 induced quiescence and autophagy with a favorable toxicology and drug distribution profile. When combined with TEM anti-tumor activity was potentiated in-vitro and in-vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Cell Cycle; Cell Line, Tumor; Disease Models, Animal; Drug Interactions; Drug Resistance, Neoplasm; Gene Amplification; Humans; Mice; Molecular Structure; N-Myc Proto-Oncogene Protein; Neuroblastoma; Pyrroles; Sirolimus; Spectrum Analysis; Xenograft Model Antitumor Assays

The objective of this study is to describe the use of targeted therapies for the treatment of advanced renal cell carcinoma (RCC) and overall survival (OS) among patients in clinical practice in the Veterans Health Administration (VHA).. A retrospective cohort of 286 patients from 24 VHA Medical Centers diagnosed with advanced clear cell RCC between Fiscal Year (FY) 2010 and FY2014 was followed through September 30, 2016. Among patients who received targeted therapy, we described the medications taken, duration of therapy, and overall survival. We also assessed the effect of the first therapy received on overall survival using Cox Proportional Hazards models.. There were 66 patients who did not receive therapy for their advanced RCC. Of the 220 treated patients, the mean (sd) number of medications received was 1.9 (1.1). The medications most commonly used first were sunitinib (61.8%), pazopanib (17.3%), and temsirolimus (10.9%). The median duration of first-line therapy was 86 days (interquartile range [IQR] 42, 210). Median total duration of therapy was 159 days (IQR 58, 397). 62.3% of patients had ≥ 1 dose of therapy held or reduced, mainly due to an adverse drug event (ADE). Median survival from the start of treatment to death was 1.08 years (IQR 0.80, 1.31). Finally, receipt of temsirolimus vs sunitinib (HR 1.95 [95%CI 1.09,3.47]) as the first targeted therapy was independently associated with an increased hazard of death.. Our analysis of targeted therapies for advanced RCC in VHA suggests duration of treatment is shorter in a real-world setting than in clinical trials, and dose reductions and ADEs are more common.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome; United States; United States Department of Veterans Affairs

Chemotherapy with docetaxel (DTX) is used for castration-resistant prostate cancer (CRPC), but it is inadequate.. We evaluated the effect of the combination treatment DTX and the mTOR inhibitor temsirolimus (TEM) in the PC3 prostate cancer cell line, by focusing on the induction of autophagy and apoptosis.. TEM induced autophagy but not apoptosis even at a high dose, whereas DTX induced apoptosis. The combination of low-dose DTX and TEM caused a 34% suppression in cell proliferation compared to monotherapy with a higher dose of DTX. The induction of apoptosis was increased by their combination. The combination with DTX overcame the induction of autophagy by TEM. The combination treatment suppressed tumor growth 72% less than the control group after 14 days of treatment in vivo.. The combination of TEM and DTX induced apoptosis by overcoming autophagy and enhanced the anticancer effect compared to monotherapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Docetaxel; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; PC-3 Cells; Prostate; Prostatic Neoplasms; Protein Kinase Inhibitors; Sirolimus

Cutaneous metastases of urological malignancies are a rare phenomenon. We present a case of a renal transplant recipient who presented with skin nodule 12 years posttransplant. Pathohistologic evaluation revealed metastasis from the renal adenocarcinoma. The patient was treated with temsirolimus and later with sorafenib; however, he died 13 months after the initial presentation with a functional renal allograft.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Sirolimus; Skin Neoplasms; Transplant Recipients; Transplantation, Homologous

Topics: Antineoplastic Agents; Autophagy; Everolimus; Humans; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

To study the prevalence of hypogonadism in male patients with metastatic renal cell carcinoma (mRCC) starting with targeted therapies and the impact of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) sunitinib and pazopanib on the luteinizing hormone (LH)/testosterone (TT)-axis.. Male mRCC patients starting with targeted therapies were prospectively included in this study. TT- and LH-levels were sampled at start as well as during systemic therapy. Endpoints of the study were gonadal status (TT- and LH-levels) at start of targeted therapy and TT- and LH-evolution during targeted therapy.. Sixty-three patients were included in this study. At start of targeted therapy, 30% of patients were eugonadal and 48% had secondary hypogonadism. Decreased TT- and increased LH-levels were associated with inflammatory state and poor prognosis. During sunitinib therapy, TT-levels decreased with 32% (p = 0.004) and LH-levels with 14% (p = 0.03). TT-levels were 13% lower (p = 0.007) and LH-levels 15% lower (p = 0.004) on day 28 compared to day 1. In four patients, a dramatic TT decrease was observed shortly after starting sunitinib. In patients treated with pazopanib, no impact on TT- or LH-levels was observed.. Hypogonadism is a frequent finding in male mRCC-patients at start of targeted therapies. In contrast to pazopanib, during sunitinib therapy, TT- and LH-levels tend to decrease, leading to an increased incidence of secondary hypogonadism.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Cross-Sectional Studies; Humans; Hypogonadism; Indazoles; Kidney Neoplasms; Luteinizing Hormone; Male; Middle Aged; Molecular Targeted Therapy; Prevalence; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib; Testosterone; Vascular Endothelial Growth Factor A

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

The evaluation of glucose metabolic activity in immune cells is becoming an increasingly standard task in immunological research. In this study, we described a sensitive, inexpensive, and non-radioactive assay for the direct and rapid measurement of the metabolic activity of CD4+ T cells in culture. A portable, custom-built Cell Culture Metabolite Biosensor device was designed to measure the levels of acidification (a proxy for glycolysis) in cell-free CD4+ T cell culture media. In this assay, ex vivo activated CD4+ T cells were incubated in culture medium and mini electrodes were placed inside the cell free culture filtrates in 96-well plates. Using this technique, the inhibitors of glycolysis were shown to suppress acidification of the cell culture media, a response similar to that observed using a gold standard lactate assay kit. Our findings show that this innovative biosensor technology has potential for applications in metabolic research, where acquisition of sufficient cellular material for ex vivo analyses presents a substantial challenge.

Topics: Biosensing Techniques; CD4-Positive T-Lymphocytes; Chromones; Electrochemical Techniques; Electrodes; Glucose; Glycolysis; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Morpholines; Signal Processing, Computer-Assisted; Sirolimus

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates nutrients to execute cell growth. We hypothesized that mTOR is influential in the intervertebral disc-largest avascular, low-nutrient organ. Our objective was to identify the optimal mTOR inhibitor for treating human degenerative disc disease.. mTOR complex 1 (mTORC1) regulates p70/ribosomal S6 kinase (p70/S6K), negatively regulates autophagy, and is controlled by Akt. Akt is controlled by phosphatidylinositol 3-kinase (PI3K) and mTOR complex 2 (mTORC2). mTORC1 inhibitors-rapamycin, temsirolimus, everolimus, and curcumin, mTORC1&mTORC2 inhibitor-INK-128, PI3K&mTOR inhibitor-NVP-BEZ235, and Akt inhibitor-MK-2206-were applied to human disc nucleus pulposus (NP) cells. mTOR signaling, autophagy, apoptosis, senescence, and matrix metabolism were evaluated.. mTORC1 inhibitors decreased p70/S6K but increased Akt phosphorylation, promoted autophagy with light chain 3 (LC3)-II increases and p62/sequestosome 1 (p62/SQSTM1) decreases, and suppressed pro-inflammatory interleukin-1 beta (IL-1β)-induced apoptotic terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity (versus rapamycin, 95% confidence interval (CI) -0.431 to -0.194; temsirolimus, 95% CI -0.529 to -0.292; everolimus, 95% CI -0.477 to -0.241; curcumin, 95% CI -0.248 to -0.011) and poly (ADP-ribose) polymerase (PARP) and caspase-9 cleavage, senescent senescence-associated beta-galactosidase (SA-β-gal) positivity (versus rapamycin, 95% CI -0.437 to -0.230; temsirolimus, 95% CI -0.534 to -0.327; everolimus, 95% CI -0.485 to -0.278; curcumin, 95% CI -0.210 to -0.003) and p16/INK4A expression, and catabolic matrix metalloproteinase (MMP) release and activation. Meanwhile, dual mTOR inhibitors decreased p70/S6K and Akt phosphorylation without enhanced autophagy and suppressed apoptosis, senescence, and matrix catabolism. MK-2206 counteracted protective effects of temsirolimus. Additional disc-tissue analysis found relevance of mTOR signaling to degeneration grades.. mTORC1 inhibitors-notably temsirolimus with an improved water solubility-but not dual mTOR inhibitors protect against inflammation-induced apoptosis, senescence, and matrix catabolism in human disc cells, which depends on Akt and autophagy induction.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Autophagy; Benzoxazoles; beta-Galactosidase; Cellular Senescence; Curcumin; Everolimus; Extracellular Matrix; Female; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Inflammation; Male; Matrix Metalloproteinases; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Microtubule-Associated Proteins; Middle Aged; Nucleus Pulposus; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Quinolines; Ribosomal Protein S6 Kinases, 70-kDa; Sequestosome-1 Protein; Sirolimus

Topics: Humans; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Sirolimus; Urinary Bladder Neoplasms

Although cilostazol was proved to have antitumor biological effects, its function in myocardial ischemia and reperfusion (I/R) injury and the underlying mechanisms were not fully illustrated yet. In this study, a rat model of I/R injury was constructed and quantitative real-time PCR, Western blot, and immunofluorescence (IF) assay were performed. Our results showed that cilostazol increased LC3 II/LC3 I ratio, reduced p62 abundance, and promoted the expressions of LAMP1, LAMP2, cathepsin B, and cathepsin D, indicating that cilostazol could activate autophagy and elevated lysosome activation. Following analysis showed that cilostazol enhanced nuclear protein expression of transcription factor EB (TFEB), an important regulator of autophagy-lysosome pathway. Furthermore, CCI-779, an inhibitor of TFEB, could reverse the effects of cilostazol on autophagic activity and lysosome activation. Importantly, cilostazol suppressed I/R injury-induced apoptosis by decreasing the cleavage of caspase 3 and PARP. Enzyme-linked immunosorbent assay showed that cilostazol reduced the serum levels of CTn1 and CK-MB and decreased infract size caused by I/R injuries. Altogether this study suggested that cilostazol protects against I/R injury by regulating autophagy, lysosome, and apoptosis in a rat model of I/R injury. The protective mechanism of cilostazol was partially through increasing the transcriptional activity of TFEB.

Topics: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cilostazol; Disease Models, Animal; Lysosomes; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Sirolimus

Temsirolimus is effective in the treatment for metastatic non-clear cell renal cell carcinoma (nccRCC) with poor prognosis. We aim to investigate the efficacy and tolerability of temsirolimus in treatment of naïve Asian patients with metastatic/recurrent nccRCC.. From January 2008 to July 2017, data of treatment-naïve, metastatic/recurrent nccRCC patients, who were treated with temsirolimus according to the standard protocol, were collected. The primary end-point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate (ORR), and tolerability of temsirolimus.. Forty-four metastatic/recurrent nccRCC patients, 10 from prospective and 34 from retrospective groups, were enrolled; 24 patients (54%) were papillary type, and other histology subtypes included 11 chromophobes (25%), two collecting ducts (5%), one Xp11.2 translocation (2%), and six others (14%). The median PFS and OS were 7.6 months and 17.6 months, res-pectively. ORR was 11% and disease control rate was 83%. Patients with prior nephrectomy had longer PFS (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.06 to 0.42; p < 0.001) and OS (HR, 0.15; 95% CI, 0.05 to 0.45; p < 0.001). Compared to favorable/intermediate prognosis group, poor prognosis group had shorter median PFS (4.7 months vs. 7.6 months [HR, 2.91; 95% CI, 1.39 to 6.12; p=0.005]) and median OS (9.2 months vs. 17.6 months [HR, 2.84; 95% CI, 1.23 to 6.56; p=0.015]).. Temsirolimus not only benefits poor-risk nccRCC patients, but it is also effective in favorable or intermediate-risk group in Asians. Temsirolimus was well-tolerated with manageable adverse events.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prospective Studies; Republic of Korea; Retrospective Studies; Sirolimus; Survival Analysis; Treatment Outcome; Young Adult

The PI3K/AKT/mTOR pathway and autophagy are known to play important roles in cancer radioresistance. The aim of the present study was to investigate whether the combination of temsirolimus (TEM), an mTOR inhibitor, and chloroquine (CQ), an autophagy inhibitor, can increase radiosensitivity in colorectal cancer (CRC) cells. The efficacies of TEM and/or CQ as radiosensitizers were examined using clonogenic assays in CRC cell lines SW480 and HT‑29. The expression levels of the phosphorylated isoforms of S6 and 4E‑BP1, downstream proteins of mTOR, as well as the expression levels of p62 and LC3, autophagy‑related proteins, were assessed by western blot analysis. The formation of acidic organelles was detected in acridine orange‑stained cells. Apoptosis and caspase activity were assessed using flow cytometry. The results revealed that ionizing radiation (IR) activated the downstream proteins of mTOR and induced autophagy. In the clonogenic assays, neither TEM nor CQ influenced the efficacy of IR, whereas their combination significantly increased the dose‑dependent efficacy of IR. TEM inhibited phosphorylation of the downstream proteins of mTOR and induced autophagy. CQ inhibited autophagy in the late phase and did not influence the downstream proteins of mTOR. TEM and CQ inhibited both the phosphorylation of downstream proteins of mTOR and autophagy. Cell death analysis revealed that the combination of TEM and CQ strongly induced apoptosis in cells exposed to IR. In conclusion, the combination of TEM and CQ increased radiosensitivity in CRC cells through co‑inhibition of mTOR and autophagy.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chloroquine; Colorectal Neoplasms; HT29 Cells; Humans; Microtubule-Associated Proteins; Phosphorylation; Radiation-Sensitizing Agents; Ribosomal Protein S6 Kinases; RNA-Binding Proteins; Sirolimus

Mucositis is often experienced in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies. This might impair daily quality of life and lead to dose reduction, discontinuation, or treatment shift. We assessed the effect of folic acid to reduce mucositis.. Patients treated with systemic therapy for mRCC who developed Grade ≥2 mucositis according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) received oral folic acid to reduce mucositis. The medical charts were retrospectively reviewed.. A total of 77 patients had Grade ≥2 mucositis during therapy with sunitinib (n = 29), pazopanib (n = 24), everolimus (n = 10), axitinib (n = 4), temsirolimus (n = 3), interleukin-2/interferon-α (n = 3), cabozantinib (n = 2), bevacizumab (n = 1), and nivolumab (n = 1). Given in doses of 1 to 5 mg daily, folic acid significantly reduced mucositis, mean CTCAE grade 0.88 (95% confidence interval [CI], 0.74-1.03) versus 2.38 (95% CI, 2.26-2.54; P < .0001). Stratified according to treatment, folic acid significantly reduced mucositis grade for sunitinib (0.97 [95% CI, 0.75-1.18] vs. 2.45 [95% CI, 2.23-2.67], P < .0001), pazopanib (0.96 [95% CI, 0.67-1.25] vs. 2.20 [2.03-2.38], P < .0001), everolimus (0.60 [95% CI, 0.10-1.10] vs. 2.60 [95% CI, 2.23-2.97], P < .0001), and other treatments (0.79 [95% CI, 0.38-1.19] vs. 2.36 [95% CI, 2.07-2.64], P < .0001). Of the 77 patients, 8 (10%) patients received dose reduction. Overall progression-free survival was 14 months and overall survival was 31 months.. Folic acid reduced mucositis in mRCC patients receiving systemic therapy. This finding needs prospective validation. A double-blind, placebo-controlled prospective evaluation of folic acid is ongoing (NCT03581773).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Everolimus; Female; Folic Acid; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Sunitinib; Treatment Outcome

Rapamycin (Rap) and its derivatives, called rapalogs, are being explored in clinical trials targeting cancer and neurodegeneration. The underlying mechanisms of Rap actions, however, are not well understood. Mechanistic target of rapamycin (mTOR), a lysosome-localized protein kinase that acts as a critical regulator of cellular growth, is believed to mediate most Rap actions. Here, we identified mucolipin 1 (transient receptor potential channel mucolipin 1 [TRPML1], also known as MCOLN1), the principle Ca2+ release channel in the lysosome, as another direct target of Rap. Patch-clamping of isolated lysosomal membranes showed that micromolar concentrations of Rap and some rapalogs activated lysosomal TRPML1 directly and specifically. Pharmacological inhibition or genetic inactivation of mTOR failed to mimic the Rap effect. In vitro binding assays revealed that Rap bound directly to purified TRPML1 proteins with a micromolar affinity. In both healthy and disease human fibroblasts, Rap and rapalogs induced autophagic flux via nuclear translocation of transcription factor EB (TFEB). However, such effects were abolished in TRPML1-deficient cells or by TRPML1 inhibitors. Hence, Rap and rapalogs promote autophagy via a TRPML1-dependent mechanism. Given the demonstrated roles of TRPML1 and TFEB in cellular clearance, we propose that lysosomal TRPML1 may contribute a significant portion to the in vivo neuroprotective and anti-aging effects of Rap via an augmentation of autophagy and lysosomal biogenesis.

Topics: Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Calcium; Cell Nucleus; Fibroblasts; HEK293 Cells; HeLa Cells; Humans; Ion Channel Gating; Lysosomes; Models, Biological; Protein Binding; Sirolimus; TOR Serine-Threonine Kinases; Transient Receptor Potential Channels

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare hereditary kidney cancer syndrome in which affected individuals are at risk of skin and uterine leiomyomatosis and kidney cancer. HLRCC-associated kidney cancer is a lethal disease with a highly aggressive behavior, and there is no standard treatment option for metastatic disease.. Here, we report a 29-year-old patient with a locally advanced HLRCC-assiciated RCC. He was administrated temsirolimus initially, then underwent surgical removal of kidney, retroperitoneal lymph nodes, inferior vena cava and tumor thrombi. Unfortunately, multiple liver metastases were confirmed 1 month after surgery, so axitinib was given but failed immediately. We tried bevacizumab plus erlotinib, which achieved long-term good response lasting more than 18 months. He is alive with disease and maintains bevacizumab plus erlotinib treatment.. The promising results obtained in this patient suggest that combined bevacizumab plus erlotinib may offer a valid treatment option for advanced HLRCC-associated kidney cancer, even after failures of mTOR inhibitor and/or VEGFR TKI based therapies.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Erlotinib Hydrochloride; Humans; Kidney Neoplasms; Leiomyomatosis; Male; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Sirolimus; Skin Neoplasms; Time Factors; Treatment Failure; Uterine Neoplasms

Targeting the mammalian target of rapamycin (mTOR) is a promising strategy for cancer therapy. Temsirolimus, a FDA-approved anticancer drug with efficacy in certain solid tumors and hematologic malignancies, is a potent mTOR inhibitor. In this work, we are the first to provide preclinical evidence that temsirolimus is an attractive candidate for retinoblastoma treatment as a dual inhibitor of retinoblastoma and angiogenesis. We show that temsirolimus selectively inhibits growth, survival and migration of retinoblastoma cells while sparing normal retinal and fibroblast cells, with IC

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Line, Tumor; Cells, Cultured; Endothelial Cells; Humans; Mice; Neovascularization, Pathologic; Retinal Neoplasms; Retinoblastoma; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

Parkinson's disease (PD) is a disorder caused by degeneration of dopaminergic neurons. At the moment, there is no cure. Recent studies have shown that autophagy may have a protective function against the advance of a number of neurodegenerative diseases. Temsirolimus is an analogue of rapamycin that induces autophagy by inhibiting mammalian target of rapamycin complex 1. For this purpose, in the present study we investigated the neuroprotective effects of temsirolimus (5 mg/kg intraperitoneal) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP) neurotoxicity in in vivo model of PD. At the end of the experiment, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Treatment with temsirolimus significantly ameliorated behavioral deficits, increased the expression of specific markers of PD such as tyrosine hydroxylase, dopamine transporter, as well as decreased the upregulation of α-synuclein in the substantia nigra after MPTP induction. Furthermore, Western blot and immunohistochemistry analysis showed that temsirolimus administration significantly increased autophagy process. In fact, treatment with temsirolimus maintained high Beclin-1, p62, and microtubule-associated protein 1A/1B-light chain 3 expression and inhibited the p70S6K expression. In addition, we showed that temsirolimus has also anti-inflammatory properties as assessed by the significant inhibition of the expression of mitogen-activated protein kinases such as p-JNK, p-p38, and p-ERK, and the restored levels of neurotrophic factor expression such as BDNF and NT-3. On the basis of this evidence, we clearly demonstrate that temsirolimus is able to modulate both the autophagic process and the neuroinflammatory pathway involved in PD, actions which may underlie its neuroprotective effect.

Topics: Animals; Autophagy; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Neuroprotective Agents; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

Topics: Antineoplastic Agents; Binding Sites; Calorimetry; Circular Dichroism; Fluorescence; Humans; Molecular Docking Simulation; Protein Binding; Protein Structure, Secondary; Serum Albumin, Human; Sirolimus; Spectrometry, Fluorescence; Thermodynamics

Accumulated data support a relationship between mood disorders and cellular plasticity and resilience, some suggesting relevance to autophagy. Our previous data show that pharmacological enhancement of autophagy results in antidepressant-like effects in mice. The current study was designed to further examine the effects of autophagy enhancement on mood by testing the effects of subchronic treatment with the mammalian target of rapamycin (mTOR) inhibitors and autophagy enhancers rapamycin and temsirolimus in a model for mania and in a model for antidepressant action, respectively. The results show that rapamycin reduced mania-like aggression and reward-seeking behaviors, with no effects on locomotion. Temsirolimus reduced depression-related immobility in the forced-swim test without effects on locomotion in the open field or on anxiety-related measures in the elevated plus maze. Taken together with our previous findings, these data support the notion that enhancing autophagy may have mood-stabilizing effects.

Topics: Affect; Aggression; Animals; Antidepressive Agents; Antimanic Agents; Anxiety; Anxiety Disorders; Autophagy; Behavior, Animal; Depression; Depressive Disorder; Male; Mice; Mice, Inbred ICR; Sirolimus

Cannabis affects cognitive performance through the activation of the endocannabinoid system, and the molecular mechanisms involved in this process are poorly understood. Using the novel object-recognition memory test in mice, we found that the main psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), alters short-term object-recognition memory specifically involving protein kinase C (PKC)-dependent signaling. Indeed, the systemic or intra-hippocampal pre-treatment with the PKC inhibitors prevented the short-term, but not the long-term, memory impairment induced by THC. In contrast, systemic pre-treatment with mammalian target of rapamycin complex 1 inhibitors, known to block the amnesic-like effects of THC on long-term memory, did not modify such a short-term cognitive deficit. Immunoblot analysis revealed a transient increase in PKC signaling activity in the hippocampus after THC treatment. Thus, THC administration induced the phosphorylation of a specific Ser residue in the hydrophobic-motif at the C-terminal tail of several PKC isoforms. This significant immunoreactive band that paralleled cognitive performance did not match in size with the major PKC isoforms expressed in the hippocampus except for PKCθ. Moreover, THC transiently enhanced the phosphorylation of the postsynaptic calmodulin-binding protein neurogranin in a PKC dependent manner. These data demonstrate that THC alters short-term object-recognition memory through hippocampal PKC/neurogranin signaling.

Topics: Animals; Anisomycin; Dizocilpine Maleate; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Hippocampus; Isoenzymes; Male; Memory, Short-Term; Mice; Microinjections; Neurogranin; Phenols; Phosphorylation; Piperidines; Protein Kinase C; Quinoxalines; Rimonabant; Signal Transduction; Sirolimus

In our study, we have characterized the prefibrillar aggregates of human serum albumin (HSA) induced by temsirolimus, anti-renal cancer drug. Molecular docking was retorted to confirm binding of HSA and temsirolimus. Temsirolimus caused the structural transition of native HSA to non-native species after prolonged incubation of 20 days. These non-native species were characterized as prefibrillar aggregates as evident by decreased intrinsic fluorescence and enhanced 8-anilino-1-naphthalene-sulphonic acid (ANS) fluorescence. Further, enhanced thioflavin T fluorescence and shift in congo red (CR) spectra of temsirolimus-incubated HSA as compared to native HSA are suggestive of global transition of HSA in presence of temsirolimus towards prefibrillar aggregates. Circular dichroism spectroscopy revealed α to β transition upon prolonged incubation with temsirolimus suggesting the formation of prefibrillar aggregates as aggregates are known to possess high β content. Scanning electron microscopy confirmed these non-native species to be prefibrillar aggregates evident by observed sheath-like structures. Comet assay was retorted to confirm genotoxic nature of these prefibrillar aggregates; DNA damage was observed for temsirolimus-incubated HSA confirming the genotoxic nature of prefibrillar aggregates. These prefibrillar aggregates are observed at heart of many pathological conditions, thus making our study clinically significant.

Topics: Antineoplastic Agents; Circular Dichroism; Humans; Kidney Neoplasms; Microscopy, Electron, Scanning; Molecular Docking Simulation; Protein Aggregates; Protein Binding; Protein Structure, Secondary; Serum Albumin, Human; Sirolimus; Spectrometry, Fluorescence

In rheumatoid arthritis (RA), activated synovial fibroblasts have the ability to invade joint cartilage, actively contributing to joint destruction in RA. The mechanisms underlying this cell migration and invasion remain unclear. Our previous results and data from the GEO profile indicate that the L-type amino acid transporter gene, LAT1, is overexpressed in the synovium of RA. To identify its potential role in RA, fibroblast-like synoviocytes (FLS) from patients with RA were used to determine the effects of suppressing the LAT1 genes using RNA interference and the LAT inhibitor, BCH. We found that BCH exposure reduced the phosphorylation of mTOR and its downstream target 4EBP1, radiolabeled leucine uptake, and migration of RA FLS. LAT1 silencing by siRNA presented effects similar to BCH inhibition. Treatment of cells with IL-17 stimulated the expression of LAT1. In contrast, applying an inhibitor of mTOR pathway, temsirolimus, or silencing eIF4E neutralized the stimulation of IL-17 on LAT1. BCH and siLAT1 also resulted in lower IL-17-stimulated leucine uptake and cell migration. These results suggest that the migration of RA FLS is aggravated by IL-17-mediated overexpression of LAT1 via mTOR/4E-BP1 pathway. In conclusion, further investigation is warranted into LAT1 as a potential target for drug therapies aimed at attenuating migration of transformed-appearing fibroblasts and subsequently preventing further erosion of bone and cartilage.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Amino Acids, Cyclic; Arthritis, Rheumatoid; Cell Cycle Proteins; Cell Movement; Cells, Cultured; Female; Fibroblasts; Gene Expression; Gene Expression Regulation; Humans; Leucine; Middle Aged; Phosphoproteins; RNA, Small Interfering; Signal Transduction; Sirolimus; Synovial Membrane; Synoviocytes; TOR Serine-Threonine Kinases

Hippo/YAP signaling plays pleiotropic roles in the regulation of cell proliferation and differentiation during organogenesis and tissue repair. Herein we demonstrate increased YAP activity in respiratory epithelial cells in lungs of patients with idiopathic pulmonary fibrosis (IPF), a common, lethal form of interstitial lung disease (ILD). Immunofluorescence staining in IPF epithelial cells demonstrated increased nuclear YAP and loss of MST1/2. Bioinformatic analyses of epithelial cell RNA profiles predicted increased activity of YAP and increased canonical mTOR/PI3K/AKT signaling in IPF. Phospho-S6 (p-S6) and p-PTEN were increased in IPF epithelial cells, consistent with activation of mTOR signaling. Expression of YAP (S127A), a constitutively active form of YAP, in human bronchial epithelial cells (HBEC3s) increased p-S6 and p-PI3K, cell proliferation and migration, processes that were inhibited by the YAP-TEAD inhibitor verteporfin. Activation of p-S6 was required for enhancing and stabilizing YAP, and the p-S6 inhibitor temsirolimus blocked nuclear YAP localization and suppressed expression of YAP target genes CTGF, AXL, and AJUBA (JUB). YAP and mTOR/p-S6 signaling pathways interact to induce cell proliferation and migration, and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF.

Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Cell Culture Techniques; Cell Differentiation; Cell Movement; Cell Proliferation; Epithelial Cells; Hepatocyte Growth Factor; Hippo Signaling Pathway; Humans; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial; Membrane Proteins; Oncogene Protein v-akt; Organogenesis; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; PTEN Phosphohydrolase; Ribosomal Protein S6 Kinases; Serine-Threonine Kinase 3; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors; Tumor Suppressor Proteins; Verteporfin; YAP-Signaling Proteins

Cancer Tissue Heterogeneity is an important consideration in cancer research as it can give insights into the causes and progression of cancer. It is known to play a significant role in cancer cell survival, growth and metastasis. Determining the compositional breakup of a heterogeneous cancer tissue can also help address the therapeutic challenges posed by heterogeneity. This necessitates a low cost, scalable algorithm to address the challenge of accurate estimation of the composition of a heterogeneous cancer tissue.. In this paper, we propose an algorithm to tackle this problem by utilizing the data of accurate, but high cost, single cell line cell-by-cell observation methods in low cost aggregate observation method for heterogeneous cancer cell mixtures to obtain their composition in a Bayesian framework.. The algorithm is analyzed and validated using synthetic data and experimental data. The experimental data is obtained from mixtures of three separate human cancer cell lines, HCT116 (Colorectal carcinoma), A2058 (Melanoma) and SW480 (Colorectal carcinoma).. The algorithm provides a low cost framework to determine the composition of heterogeneous cancer tissue which is a crucial aspect in cancer research.

Topics: Algorithms; Antineoplastic Agents; Bayes Theorem; Cell Count; Cell Line, Tumor; Computer Simulation; Humans; Lapatinib; Neoplasms; Probability; Sirolimus

mTOR inhibitors are used to treat renal cell carcinoma (RCC). Treatment response is variable and appears to correlate with genetic alterations that activate mTOR signaling. Recently, everolimus was suggested to be more effective than sunitinib in chromophobe RCC (chRCC), a tumor with frequent mTOR pathway defects. This report presents the genomic and functional characterization of a metastatic chRCC that showed complete response at metastatic sites and 80% reduction in primary tumor size upon temsirolimus treatment. After surgery, the patient remained disease-free for 8 years after temsirolimus therapy. Whole-exome sequencing (WES) revealed 2 somatic variants in

Topics: Adult; Antineoplastic Agents; Biopsy; Carcinoma, Renal Cell; DNA Mutational Analysis; Female; Humans; Immunohistochemistry; Kidney Neoplasms; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome; Tuberous Sclerosis Complex 2 Protein

In our present study, binding between an important anti renal cancer drug temsirolimus and human transferrin (hTF) was investigated employing spectroscopic and molecular docking approach. In the presence of temsirolimus, hyper chromaticity is observed in hTF in UV spectroscopy suggestive of complex formation between hTF and temsirolimus. Fluorescence spectroscopy revealed the occurrence of quenching in hTF in the presence of temsirolimus implying complex formation taking place between hTF and temsirolimus. Further, the mode of interaction between hTF and temsirolimus was revealed to be static by fluorescence quenching analysis at 3 different temperatures. Binding constant values obtained employing fluorescence spectroscopy depicts strong interaction between hTF and temsirolimus; temsirolimus binds to hTF at 298 K with a binding constant of .32 × 10

Topics: Antineoplastic Agents; Humans; Molecular Docking Simulation; Protein Binding; Sirolimus; Spectrometry, Fluorescence; Thermodynamics; Transferrin

Mutations in the genes necessary for the structure and function of vertebrate photoreceptor cells are associated with multiple forms of inherited retinal degeneration. Mutations in the gene encoding RHO (rhodopsin) are a common cause of autosomal dominant retinitis pigmentosa (adRP), with the Pro23His variant of RHO resulting in a misfolded protein that activates endoplasmic reticulum stress and the unfolded protein response. Stimulating macroautophagy/autophagy has been proposed as a strategy for clearing misfolded RHO and reducing photoreceptor death. We found that retinas from mice heterozygous for the gene encoding the RHO

Topics: Animals; Autophagy; Autophagy-Related Protein 5; Beclin-1; Hydroxychloroquine; Mice, Inbred C57BL; Mutation; Photoreceptor Cells, Vertebrate; Proteasome Endopeptidase Complex; Protein Folding; Proteolysis; Retinal Degeneration; Rhodopsin; Sirolimus

mTOR pathway inhibitors such as rapalogs represent a promising tool to induce functional memory CD8 T cells. In our study, we investigated the combination of temsirolimus with anticancer vaccines. Using various designs of cancer vaccines (short and long peptides or the B subunit of Shiga toxin as an antigen delivery vector) and tumor models (melanoma, lung and colon cancer), we showed that the administration of temsirolimus efficiently decreased tumor growth and enhanced tumor-specific CD8 T-cell responses induced by vaccination. Furthermore, tumor-specific CD8 T cells induced by the bi-therapy (vaccine + temsirolimus) exhibit phenotypic characteristics of central memory (CD127

Topics: Animals; Antineoplastic Agents; Cancer Vaccines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Female; Immunologic Memory; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Receptors, CCR4; Sirolimus; Vaccination

The mechanistic target of rapamycin (mTOR) is an established therapeutic target in renal cell carcinoma (RCC). Mechanisms of secondary resistance to rapalog therapy in RCC have not been studied previously. We identified six patients with metastatic RCC who initially responded to mTOR inhibitor therapy and then progressed, and had pre-treatment and post-treatment tumor samples available for analysis. We performed deep whole exome sequencing on the paired tumor samples and a blood sample. Sequence data was analyzed using Mutect, CapSeg, Absolute, and Phylogic to identify mutations, copy number changes, and their changes over time. We also performed in vitro functional assays on PBRM1 in RCC cell lines. Five patients had clear cell and one had chromophobe RCC. 434 somatic mutations in 416 genes were identified in the 12 tumor samples. 201 (46%) of mutations were clonal in both samples while 129 (30%) were acquired in the post-treatment samples. Tumor heterogeneity or sampling issues are likely to account for some mutations that were acquired in the post-treatment samples. Three samples had mutations in TSC1; one in PTEN; and none in MTOR. PBRM1 was the only gene in which mutations were acquired in more than one post-treatment sample. We examined the effect of PBRM1 loss in multiple RCC cell lines, and could not identify any effect on rapalog sensitivity in in vitro culture assays. We conclude that mTOR pathway gene mutations did not contribute to rapalog resistance development in these six patients with advanced RCC. Furthermore, mechanisms of resistance to rapalogs in RCC remain unclear and our results suggest that PBRM1 loss may contribute to sensitivity through complex transcriptional effects.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; DNA-Binding Proteins; Drug Resistance, Neoplasm; Epigenesis, Genetic; Everolimus; Exome Sequencing; Female; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Humans; Kidney Neoplasms; Male; Middle Aged; Mutation; Nuclear Proteins; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

The mechanistic target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, have widened therapeutic options to treat renal cell carcinoma (RCC). However, chronic treatment with these inhibitors often induces resistance, leading to therapeutic failure.. The natural compound, sulforaphane (SFN), was added to an everolimus based regime in vitro in the hopes of preventing resistance development.. A panel of RCC cell lines (A498, Caki-1, KTCTL-26) was treated with everolimus or SFN or with an everolimus-SFN-combination, either short- (24h) or long-term (8 weeks), and cell growth, proliferation, apoptosis, and cell cycle phases were measured. The cell cycle regulating proteins cdk1, cdk2, cyclin A, cyclin B, akt and raptor (both total and activated) were also evaluated.. Short-term incubation with everolimus (1nM) or SFN (5µM) significantly reduced RCC cell growth. Additive effects on tumor growth and proliferation were evoked by the SFN-everolimus combination. Long-term everolimus-incubation led to resistance development in Caki-1 cells, evidenced by elevated growth and proliferation, associated with an increased percentage of G2/M (non-synchronized cell model) or S-phase (synchronized cell model) cells. Molecular analysis revealed up-regulation of the cdk1-cyclin B and cdk2-cyclin A axis, along with elevated phosphorylation of the mTOR sub-member, raptor. In contrast, resistance development was not observed with the long-term combination of SFN-everolimus. The combination suppressed Caki-1 growth and proliferation, and was associated with an increase in G0/G1-phase cells, diminished cdk1 and akt (both total and activated), cyclin B and raptor expression.. Adding SFN to an everolimus based RCC treatment regimen in vitro delayed resistance development observed with chronic everolimus monotherapy. Ongoing in vivo studies are necessary to verify the in vitro data.

Topics: Anticarcinogenic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Everolimus; Humans; Isothiocyanates; Sirolimus

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway is crucial for tumor survival, proliferation, and progression, making it an attractive target for therapeutic intervention. In glioblastoma, activated mammalian target of rapamycin promotes invasive phenotype and correlates with poor patient survival. A wide range of mammalian target of rapamycin inhibitors are currently being evaluated for cytotoxicity and anti-proliferative activity in various tumor types but are not explored sufficiently for controlling tumor invasion and recurrence. We recently reported that mammalian target of rapamycin inhibitors-rapamycin, temsirolimus, torin 1, and PP242-suppressed invasion and migration promoted by tumor necrosis factor-alpha and phorbol-myristate-acetate in glioblastoma cells. As aggressive invasion and migration of tumors are associated with mesenchymal and stem-like cell properties, this study aimed to examine the effect of mammalian target of rapamycin inhibitors on these features in glioblastoma cells. We demonstrate that temsirolimus and torin 1 effectively reduced the constitutive as well as phorbol-myristate-acetate/oncostatin-M-induced expression of mesenchymal markers (fibronectin, vimentin, and YKL40) and neural stem cell markers (Sox2, Oct4, nestin, and mushashi1). The inhibitors significantly abrogated the neurosphere-forming capacity induced by phorbol-myristate-acetate and oncostatin-M. Furthermore, we demonstrate that the drugs dephosphorylated signal transducer and activator transcription factor 3, a major regulator of mesenchymal and neural stem cell markers implicating the role of signal transducer and activator transcription factor 3 in the inhibitory action of these drugs. The findings demonstrate the potential of mammalian target of rapamycin inhibitors as "stemness-inhibiting drugs" and a promising therapeutic approach to target glioma stem cells.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Fibronectins; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Naphthyridines; Neoplasm Recurrence, Local; Neural Stem Cells; Oncostatin M; Phosphatidylinositol 3-Kinases; Signal Transduction; Sirolimus; STAT3 Transcription Factor; Tetradecanoylphorbol Acetate; TOR Serine-Threonine Kinases; Vimentin

Metabolic alteration constitutes a hallmark of cancer. Glycolysis and antioxidant pathways in kidney cancer are elevated, with frequent mutation of the VHL gene. Intratumor genetic heterogeneity has been recently demonstrated in kidney cancer. However, intratumor metabolic heterogeneity has not been investigated. Here, we used global metabolomics analysis and tissue slice tracer studies to demonstrate that different portions of a human primary kidney tumor possess different metabolic characteristics and drug sensitivity. Pyruvate levels were elevated and pyruvate metabolism was altered in some tumor sections. These observations indicated that pyruvate metabolism may constitute a possible vulnerability of kidney cancer; indeed, pyruvate stimulated the growth of primary kidney cancer cells and pharmacological inhibition of pyruvate transporters slowed the growth of patient-derived kidney tumors in mice. These findings deepen our understanding of the intratumor metabolic heterogeneity of kidney cancer and may inform novel therapeutic approaches in human kidney cancer.

Topics: Acrylates; Animals; Antineoplastic Agents; Cells, Cultured; Female; Glycolysis; Humans; Kidney Neoplasms; Metabolomics; Mice; Pyruvic Acid; Sirolimus; Xenograft Model Antitumor Assays

The BRAFV600E inhibitor vemurafenib achieves remarkable clinical responses in patients with BRAF-mutant melanoma, but its effects are limited by the onset of drug resistance. In the case of resistance, chemotherapy can still be applied as second line therapy. However, it yields low response rates and strategies are urgently needed to potentiate its effects. In a previous study, we showed that the inhibition of the PI3K-AKT-mTOR pathway significantly increases sensitivity of melanoma cells to chemotherapeutic drugs (J. Invest. Dermatol. 2009, 129, 1500). In this study, the combination of the mTOR inhibitor temsirolimus with the chemotherapeutic agent temozolomide significantly increases growth inhibition and apoptosis in melanoma cells compared to temsirolimus or temozolomide alone. The combination of temozolomide with temsirolimus is not only effective in established but also in newly isolated and vemurafenib-resistant metastatic melanoma cell lines. These effects are associated with the downregulation of the anti-apoptotic protein Mcl-1 and the upregulation of the Wnt antagonist Dickkopf homologue 1 (DKK1). Knock-down of DKK1 suppresses apoptosis induction by the combination of temsirolimus and temozolomide. These data suggest that the inhibition of the mTOR pathway increases sensitivity of melanoma cells towards temozolomide. Chemosensitisation is associated with enhanced expression of the Wnt antagonist DKK1.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dacarbazine; Early Growth Response Protein 1; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Transfer Techniques; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Lentivirus; Melanoma; Membrane Proteins; Oligonucleotide Array Sequence Analysis; Signal Transduction; Sirolimus; Skin; Skin Neoplasms; Sulfonamides; Temozolomide; TOR Serine-Threonine Kinases; Vemurafenib

To assess the role of first-line Molecular Targeted Therapies (MTTs) in Advanced chordoma (AC) patients.. Retrospective study of 80 patients treated between January 2004 and December 2015 at 15 major French Sarcoma or Neurooncology Centres.. The sex ratio M/F was 46/34. The median age was 59 (6-86) years. The primary sites were the sacrum (50, 62.5%), mobile spine (12, 15.0%), and skull base (18, 22.5%). Metastases were present in 28 patients (36.0%). The first line of MTTs consisted of imatinib (62, 77.5%), sorafenib (11, 13.7%), erlotinib (5, 6.3%), sunitinib (1, 1.2%) and temsirolimus (1, 1.2%). The reported responses were: partial response (5, 6.3%), stable disease (58, 72.5%), or progressive disease (10, 12.5%). Symptomatic improvement was seen in 28/66 assessable patients (42.4%) and was associated with an objective response occurrence (p = 0.005), imatinib (p = 0.020) or erlotinib use (p = 0.028). The median progression-free survival (PFS) was 9.4°months (95% CI, [6.8-16.1]). Two independent factors of poor prognosis for PFS were identified: a skull-based primary location (HR = 2.5, p = 0.019), and the interval between diagnosis and MTT of <52months (HR = 2.8, p < 0.001). The median overall survival (OS) was 4.4°years (95% CI, [3.8-5.6]). Four independent factors of poor prognosis for OS were identified: the presence of liver metastases (HR = 13.2, p < 0.001), pain requiring opioids (HR = 2.9, p = 0.012), skull-based primary location (HR = 19.7, p < 0.001), and prior radiotherapy (photon alone) (HR = 2.5, p = 0.024). The PFS and OS did not significantly differ between the MTT.. The prognostic factors identified require validation in an independent database but are potently useful to guide treatment decisions and design further clinical trials.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Child; Chordoma; Erlotinib Hydrochloride; Female; France; Humans; Imatinib Mesylate; Indoles; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrroles; Retrospective Studies; Sirolimus; Skull Base Neoplasms; Sorafenib; Sunitinib; Treatment Outcome; Young Adult

The mTor-inhibitor temsirolimus (TEM) has potent anti-tumor activities on extrahepatic colorectal metastases. Treatment of patients with advanced disease may require portal branch ligation (PBL). While PBL can induce intrahepatic tumor growth, the effect of PBL on extrahepatic metastases under TEM treatment is unknown. Therefore, we analyzed the effects of TEM treatment on extrahepatic metastases during PBL-associated liver regeneration. GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chamber of BALB/c-mice. Mice were randomized to four groups (n = 8). One was treated daily with TEM (1.5 mg/kg), PBS-treated animals served as controls. Another group underwent PBL of the left liver lobe and received daily TEM treatment. Animals with PBL and PBS treatment served as controls. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied over 14 days. In non-PBL animals TEM treatment inhibited tumor cell proliferation as well as vascularization and growth of the extrahepatic metastases. PBL did not influence tumor cell engraftment, vascularization and metastatic growth. Of interest, TEM treatment significantly reduced tumor cell engraftment, neovascularization and metastatic groth also after PBL. PBL does not counteract the inhibiting effect of TEM on extrahepatic colorectal metastatic growth.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Female; Ligation; Liver Neoplasms; Liver Regeneration; Mice, Inbred BALB C; Neoplasm Invasiveness; Neovascularization, Pathologic; Portal Vein; Sirolimus; Tumor Burden; Xenograft Model Antitumor Assays

Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity.. Pharmacokinetic profiles were obtained for 16 patients with bladder cancer after intravenous infusion of 25 mg temsirolimus. Non-compartmental analysis was performed to calculate the pharmacokinetic parameters of temsirolimus and sirolimus, its main metabolite. The presence of single nucleotide polymorphisms (SNPs) in CYP3A5, ABCB1 and in their transcriptional regulator NR1I2 (PXR) was assessed by genotyping. Non-parametric statistical tests were used to assess associations between candidate SNPs and temsirolimus pharmacokinetics and toxicity.. The ratio between sirolimus AUC and temsirolimus AUC was 1.6-fold higher in patients who experienced serious toxic events (p = 0.034). The frequency of adverse events was significantly higher in patients homozygous for the NR1I2-rs6785049 A allele (OR = 0.065, p = 0.04) or NR1I2-rs3814055 C allele (OR = 0.032, p = 0.006). These NR1I2 SNPs were also predictive of temsirolimus half-life and global exposure to temsirolimus and sirolimus. Finally, the effect of the ABCB1-rs1128503, ABCB1-rs2032582 and CYP3A5*3 SNPs on sirolimus pharmacokinetics was confirmed.. Our findings suggest that SNPs of NR1I2 and its target genes CYP3A5 and ABCB1 are genetic determinants of temsirolimus pharmacokinetics and toxicity in patients with bladder cancer.

Topics: Aged; Antineoplastic Agents; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Sirolimus; Urinary Bladder Neoplasms

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus stimulates apoptosis of tumor cells and is thus therapeutically used for the treatment of diverse malignancies. On the other hand, temsirolimus has been shown to protect against apoptosis of hippocampal neurons. Similar to nucleated cells, blood platelets may enter suicidal death characterized by cell shrinkage and cell membrane scrambling. Platelet apoptosis is frequently preceded by Ca2+ entry, degranulation, integrin activation and stimulation of caspases. Those events could be triggered by collagen related peptide (CRP). The present study explored whether treatment of platelets with temsirolimus modifies platelet activation, caspase activity, platelet shrinkage, and phosphatidylserine abundance.. Platelets isolated from wild-type mice were exposed for 30 minutes to temsirolimus (40 µg/ml) without or with additional CRP (2 µg/ ml or 5 µg/ml) treatment. Flow cytometry was employed to estimate cytosolic Ca2+-activity ([Ca2+]i) from Fluo-3 fuorescence, platelet degranulation from P-selectin abundance, integrin activation from αIIbβ3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding and relative platelet volume from forward scatter.. In the absence of CRP, the administration of temsirolimus (40 µg/ml) significantly decreased [Ca2+]i, but did not significantly modify P-selectin abundance, activated αIIbβ3 integrin, annexin-V-binding, cell volume, caspase activity and aggregation. Exposure of platelets to CRP was followed by significant increase of [Ca2+]i, P-selectin abundance, αIIbβ3 integrin activity, annexin-V-binding, ROS, caspase activity and aggregation, effects significantly blunted in the presence of temsirolimus. CRP further decreased forward scatter, an effect again significantly blunted by temsirolimus.. Temsirolimus is a powerful inhibitor of platelet activation and suicidal platelet death.

Topics: Animals; Apoptosis; Blood Platelets; Carrier Proteins; Female; Male; Mice; Peptides; Platelet Activation; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Carcinoma of the collecting ductsof Bellini isa rare histological subtype of renal cell carcinoma and mostly has unfavorable prognosis. Radical nephrectomy is generally chosen for the 1st line treatment but therapeutic approaches for the metastasis/recurrence have not been established. We report a case of carcinoma of collecting ducts of Bellini in a patient receiving hemodialysis treated with temsirolimus. A 62- year-old man receiving hemodialysis was admitted to our hospital with drug-resistant anemia and high-grade cyclic fever. Computed tomography revealed the right renal tumor and multiple metastatic lung tumors. Open radical nephrectomy wasperformed. Pathological findingswere compatible with carcinoma of the collecting ducts of Bellini. He was given weekly temsirolimus treatment. The disease progressed modestly but kept the stable disease (SD) status for six months. He died of the cancer 11 months after the initial diagnosis.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Kidney Tubules, Collecting; Lung Neoplasms; Male; Middle Aged; Nephrectomy; Renal Dialysis; Sirolimus; Tomography, X-Ray Computed

Mammalian target of rapamycin (mTOR) is a pivotal regulator of cell proliferation, survival, and autophagy. Autophagy is increased in adult experimental chronic pulmonary hypertension (PHT), but its contributory role to pulmonary vascular disease remains uncertain and has yet to be explored in the neonatal animal. Notch is a major pro-proliferative pathway activated by mTOR. A direct relationship between autophagy and Notch signaling has not been previously explored. Our aim was to examine changes in mTOR-, Notch-, and autophagy-related pathways and the therapeutic effects of autophagy modulators in experimental chronic neonatal PHT secondary to chronic hypoxia.. Rat pups were exposed to normoxia or hypoxia (13% O. Exposure to hypoxia up-regulated autophagy and Notch3 signaling markers in lung, pulmonary artery (PA), and PA-derived smooth muscle cells (SMCs). Temsirolimus prevented chronic PHT and attenuated PA and SMC signaling secondary to hypoxia. These effects were replicated by DAPT. mTOR or Notch inhibition also down-regulated smooth muscle content of platelet-derived growth factor β-receptor, a known contributor to vascular remodeling. In contrast, chloroquine had no modifying effects on markers of chronic PHT. Knockdown of Beclin-1 in SMCs had no effect on hypoxia-stimulated Notch3 signaling.. mTOR-Notch3 signaling plays a critical role in experimental chronic neonatal PHT. Inhibition of autophagy did not suppress Notch signaling and had no effect on markers of chronic PHT.

Topics: Animals; Animals, Newborn; Autophagy; Cell Proliferation; Diamines; Female; Hypertension, Pulmonary; Hypoxia; Lung; Male; Myocytes, Smooth Muscle; Pulmonary Artery; Rats, Sprague-Dawley; Receptor, Notch3; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Sirolimus; Thiazoles; TOR Serine-Threonine Kinases

Cancer progression toward invasive and metastatic disease is aided by reactivation of epithelial-mesenchymal transition (EMT), involving transdifferentiation of epithelial cells into mesenchymal phenotype. This leads to increased migratory and stem cell-like features in the cells. These EMT cells are more resistant to chemotherapy and it is hypothesized that the phenomenon of autophagy induces resistance, providing a survival strategy for cells. In the present study, we induced EMT-like phenotype in renal carcinoma cells and identified corresponding higher autophagy flux in these cells. The EMT transformed cells may be a representative of the resistant cancer stem cell(CSC)-like phenotype. Autophagy was identified as a potential mechanism of cell survival in these cells thus implying that autophagy inhibition can lead to enhanced cell death. We also observed that tumor cells especially EMT transformed cells, have been 'primed' to undergo autophagy by mTOR inhibition. We observed that combined use of autophagy inhibitor and temsirolimus (TEM) improved antitumor activity against RCC in EMT transformed metastatic cells. One of the approaches for inhibiting autophagy was the use of lysosomotropic anti-malarial drug, chloroquine (CQ) and we explored the therapeutic potential of combination of CQ and the mTOR inhibitor, TEM. EMT transformed cells showed increased cell cytotoxicity when autophagy was impaired by addition CQ with TEM. This led us to conclude that inhibition of autophagy with the current therapeutic regimen could be useful in targeting the EMT transformed cells along with the bulk tumor cells in RCC.

Topics: Autophagy; Carcinoma, Renal Cell; Cell Culture Techniques; Cell Line, Tumor; Chloroquine; Epithelial-Mesenchymal Transition; Humans; Kidney Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is utilized for the treatment of malignancy. Temsirolimus is at least in part effective by triggering suicidal tumor cell death. The most common side effect of temsirolimus treatment is anemia. At least in theory, the anemia following temsirolimus treatment could result from stimulation of eryptosis, the suicidal erythrocyte death. Hallmarks of eryptosis include cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in the orchestration of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, as well as activation of staurosporine and chelerythrine sensitive protein kinase C, SB203580 sensitive p38 kinase, D4476 sensitive casein kinase 1, and zVAD sensitive caspases. The purpose of the present study was to test whether temsirolimus influences eryptosis and, if so, to shed light on the signaling involved.. Flow cytometry was employed to estimate cell volume from forward scatter, phosphatidylserine exposure at the cell surface from annexin-V-binding, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was determined from hemoglobin concentration in the supernatant.. A 48 hours exposure of human erythrocytes to temsirolimus (5 - 20 µg/ml) significantly decreased forward scatter and significantly increased the percentage of annexin-V-binding cells. Temsirolimus significantly increased Fluo3-fluorescence, DCFDA fluorescence and ceramide abundance at the erythrocyte surface. The effect of temsirolimus on annexin-V-binding was significantly blunted but not abolished by removal of extracellular Ca2+ and by addition of staurosporine (1 µM) or chelerythrine (10 µM) but not significantly modified by addition of SB203580 (2 µM), D4476 (10 µM), or zVAD (10 µM). Chelerythrine (10 µM) further significantly blunted the effect of temsirolimus on DCFDA fluorescence but not ceramide formation. Removal of extracellular Ca2+ had no effect on temsirolimus induced ROS formation or ceramide abundance.. Temsirolimus triggers eryptosis with cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry, oxidative stress, ceramide and activation of staurosporine/Chelerythrine sensitive kinase(s).

Topics: Aniline Compounds; Annexin A5; Antineoplastic Agents; Benzamides; Benzophenanthridines; Calcium; Casein Kinase I; Caspases; Ceramides; Eryptosis; Erythrocytes; Fluoresceins; Gene Expression Regulation; Hemolysis; Humans; Imidazoles; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Phosphatidylserines; Primary Cell Culture; Protein Kinase Inhibitors; Pyridines; Reactive Oxygen Species; Signal Transduction; Sirolimus; Staurosporine; TOR Serine-Threonine Kinases; Xanthenes

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Mechanistic Target of Rapamycin Complex 1; Mice; Neuroblastoma; para-Aminobenzoates; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Mechanistic target of rapamycin (mTOR) signaling is typically increased in hepatocellular carcinoma (HCC). A panel of HCC cell lines (HepG2, Hep3B and HuH6) was exposed to various concentrations of the mTOR inhibitors, everolimus and temsirolimus, in order to investigate their effects on cell growth, clonal formation, cell cycle progression, and adhesion and chemotactic migration using MTT and clonal cell growth assays, fluorometric detection of cell cycle phases and a Boyden chamber assay. In addition, integrin α and β adhesion receptors were analyzed by flow cytometry and blocking studies using function blocking monoclonal antibodies were conducted to explore functional relevance. The results demonstrated that everolimus and temsirolimus significantly suppressed HCC cell growth and clonal formation, at 0.1 or 1 nM (depending on the cell line). In addition, the number of cells in G0/G1 phase was increased in response to drug treatment, whereas the number of G2/M phase cells was decreased. Drug treatment also considerably suppressed HCC cell adhesion to immobilized collagen. Integrin profiling revealed strong expression of integrin α1, α2, α6 and β1 subtypes; and integrin α1 was upregulated in response to mTOR inhibition. Suppression of integrin α1 did not affect cell growth; however, it did significantly decrease adhesion and chemotaxis, with the influence on adhesion being greater than that on motility. Due to a positive association between integrin α1 expression and the extent of adhesion, whereby reduced receptor expression was correlated to decreased cell adhesion, it may be hypothesized that the adhesion‑blocking effects of mTOR inhibitors are not associated with mechanical contact inhibition of the α1 receptor but with integrin α1‑dependent suppression of oncogenic signaling, thus preventing tumor cell‑matrix interaction.

Topics: Antibodies, Monoclonal; Carcinoma, Hepatocellular; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Chemotaxis; Everolimus; G1 Phase Cell Cycle Checkpoints; Hep G2 Cells; Humans; Integrin alpha1; Integrins; Liver Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation

Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells. As an application for these findings, we demonstrate maximum tumor cell growth inhibition occurring only at doses which induce UPR and which have been shown to be safely achieved in human patients. These results are significant because they challenge the paradigm for the use of these drugs as anticancer agents and reveal a connection to UPR, a conserved biological response that has been implicated in tumor growth and response to therapy. As a result, eIF2 alpha phosphorylation and Xbp-1 splicing may serve as useful biomarkers of treatment response in future clinical trials using rapamycin and rapalogs.

Topics: Cell Line, Tumor; Cell Proliferation; Eukaryotic Initiation Factor-2; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA Splicing; RNA, Messenger; RNA, Ribosomal, 28S; Sarcoma; Sirolimus; Solvents; TOR Serine-Threonine Kinases; Unfolded Protein Response; X-Box Binding Protein 1

Quantitative measurement of transcription rates in live cells is important for revealing mechanisms of transcriptional regulation. This is particularly challenging when measuring the activity of RNA polymerase III (Pol III), which transcribes growth-promoting small RNAs. To address this issue, we developed Corn, a genetically encoded fluorescent RNA reporter suitable for quantifying RNA transcription in cells. Corn binds and induces fluorescence of 3,5-difluoro-4-hydroxybenzylidene-imidazolinone-2-oxime, which resembles the fluorophore found in red fluorescent protein (RFP). Notably, Corn shows high photostability, enabling quantitative fluorescence imaging of mTOR-dependent Pol III transcription. We found that, unlike actinomycin D, mTOR inhibitors resulted in heterogeneous transcription suppression in individual cells. Quantitative imaging of Corn-tagged Pol III transcript levels revealed distinct Pol III transcription 'trajectories' elicited by mTOR inhibition. Together, these studies provide an approach for quantitative measurement of Pol III transcription by direct imaging of Pol III transcripts containing a photostable RNA-fluorophore complex.

Topics: Aptamers, Nucleotide; Base Pairing; Base Sequence; Chromophore-Assisted Light Inactivation; Fluorescent Dyes; Gene Expression Regulation; HEK293 Cells; Humans; Luminescent Proteins; Nucleic Acid Conformation; Optical Imaging; Red Fluorescent Protein; RNA Polymerase III; Sirolimus; TOR Serine-Threonine Kinases; Transcription, Genetic

mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole-exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Carcinoma, Renal Cell; Denosumab; Exome Sequencing; Female; Gain of Function Mutation; Humans; Kidney Neoplasms; Liver Neoplasms; Magnetic Resonance Imaging; Mechanistic Target of Rapamycin Complex 1; Metastasectomy; Middle Aged; Mutation, Missense; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Response Evaluation Criteria in Solid Tumors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Suppressor Proteins; Ubiquitin Thiolesterase

Background Signal transduction inhibitors (STIs) have considerably improved treatment of advanced/metastasized renal cell carcinoma (mRCC). Most safety data for these drugs are derived from clinical trials. The purpose of this study was to evaluate which adverse drug reactions are documented during first-line treatments in routine clinical practice. Patients and methods The ongoing prospective German mRCC clinical registry is recruiting patients in 110 oncology and urology outpatient centers. Data from the first 250 patients who had completed first-line treatment were analyzed regarding adverse drug reactions (ADRs) documented in patients' medical records. Results Patients were older than in clinical trials and had comorbidities. Patients were treated with the STIs sunitinib (61%), temsirolimus (14%), sorafenib (10%), or bevacizumab combined with interferon (6%). About 520 ADRs were documented, of which 29% resulted in treatment modifications. The most frequently affected organ system was the gastrointestinal system. The most frequently documented ADRs were mucositis/stomatitis (14%), fatigue (14%), diarrhea (12%), and nausea (12%). Conclusions In routine practice, mRCC first-line treatments using STIs frequently lead to ADRs partly necessitating treatment modifications. The pattern of reported ADRs is similar to that reported in clinical trials, but frequencies of events differ, especially for symptoms of multifactorial origin that are not immediately associated with the treatment. These results indicate that perception and documentation of adverse reactions is different between clinical trials and routine practice, and that reviews of patients' medical records might not be the best method to assess safety in routine practice.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Diarrhea; Documentation; Fatigue; Female; Germany; Humans; Indoles; Interferons; Kidney Neoplasms; Male; Medical Oncology; Middle Aged; Nausea; Niacinamide; Phenylurea Compounds; Prospective Studies; Pyrroles; Registries; Sirolimus; Sorafenib; Stomatitis; Sunitinib

Autophagy is an intracellular catabolic mechanism for the degradation of cytoplasmic constituents in the autophagosomal-lysosomal pathway. This mechanism plays an important role in homeostasis and it is defective in certain diseases. Preceding studies have revealed that autophagy is developing as an important moderator of pathological responses associated to spinal cord injury (SCI) and plays a crucial role in secondary injury initiating a progressive degeneration of the spinal cord. Thus, based on this evidence in this study, we used two different selective inhibitors of mTOR activity to explore the functional role of autophagy in an in vivo model of SCI as well as to determine whether the autophagic process is involved in spinal cord tissue damage. We treated animals with a novel synthetic inhibitor temsirolimus and with a dual mTORC1 and mTORC2 inhibitor KU0063794 matched all with the well-known inhibitor of mTOR the rapamycin. Our results demonstrated that mTOR inhibitors could regulate the neuroinflammation associated to SCI and the results that we obtained evidently demonstrated that rapamycin and temsirolimus significantly diminished the expression of iNOS, COX2, GFAP, and re-established nNOS levels, but the administration of KU0063794 is able to blunt the neuroinflammation better than rapamycin and temsirolimus. In addition, neuronal loss and cell mortality in the spinal cord after injury were considerably reduced in the KU0063794-treated mice. Accordingly, taken together our results denote that the administration of KU0063794 produced a neuroprotective function at the lesion site following SCI, representing a novel therapeutic approach after SCI.

Topics: Animals; Apoptosis; Astrocytes; Cell Survival; Cyclooxygenase 2; Cytokines; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Morpholines; Motor Activity; Multiprotein Complexes; Nerve Tissue; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Pyrimidines; Signal Transduction; Sirolimus; Spinal Cord; Spinal Cord Injuries; TOR Serine-Threonine Kinases

Topics: Aged; Antineoplastic Agents; Arm; Axitinib; Carcinoma, Renal Cell; Fat Necrosis; Humans; Kidney Neoplasms; Male; Sirolimus; Subcutaneous Fat

It has not been well documented that the modulation of stress response mediates the efficacy of the mammalian target of rapamycin (mTOR) inhibitor in renal cell carcinoma (RCC).. The objective of this study was to investigate whether the activity of the mTOR inhibitor temsirolimus against RCC could be enhanced by OGX-011, an antisense oligodeoxynucleotide (ODN) targeting the stress-activated chaperone clusterin.. We investigated the efficacy of combined treatment with temsirolimus plus OGX-011 in a human RCC Caki-1 model focusing on the effects on apoptotic and autophagic pathways.. Although clusterin expression was increased by temsirolims, additional treatment of Caki-1 with OGX-011 significantly inhibited clusterin upregulation (p < 0.05). Combined treatment of temsirolimus and OGX-011 synergistically enhanced the sensitivity of Caki-1 to temsirolimus (p < 0.01), reducing the IC. Silencing of clusterin using OGX-011 resulted in the further enhancement of proapoptotic activity as well as the marked attenuation of the autophagic pathway induced by temsirolimus in a human RCC model. Thus, the combined use of OGX-011 could be a promising strategy through the enhanced cytotoxic activity of temsirolimus against RCC.

Topics: Animals; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Clusterin; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Sirolimus; Thionucleotides; Xenograft Model Antitumor Assays

Pediatric renal cell carcinoma (RCC) is a rare cancer that can be associated with inherited diseases including tuberous sclerosis complex (TSC) caused by germline mutations in TSC1 or TSC2. Somatic mutations in TSC1 and TSC2 have also been reported in adult RCC, which predict response to mTOR inhibitors. Here, we present the first case of RCC in a child with methylmalonic acidemia (MMA). Clinical whole exome sequencing of blood and tumor samples confirmed the diagnosis of MMA and revealed two somatic inactivating mutations in TSC2, suggesting the potential consideration of an mTOR inhibitor in the event of tumor recurrence.

Topics: Amino Acid Metabolism, Inborn Errors; Antineoplastic Agents; Carcinoma, Renal Cell; Child; Everolimus; Female; Humans; Kidney Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

The oncogenic PI3K/Akt/mTOR pathway is frequently activated in hepatocellular carcinoma (HCC). The aim of this study is to investigate the anti-HCC effect of combination of temsirolimus, an mTOR inhibitor, and adriamycin, a routinely used drug for treating HCC.. Proliferation of HCC cells exposure to temsirolimus, adriamycin, and their combination was determined using MTT assay in vitro as well as in a nude mice model in vivo. Cell apoptosis was examined using flow cytometry. Expressions of apoptosis-related proteins including caspase-9, -3, PARP, Bax, and Bcl-2 were determined using Western blotting.. Temsirolimus plus adriamycin showed an enhanced inhibitory effect on cell proliferation compared to temsirolimus or adriamycin in HCC cells PLC/PRF/5, BEL7402, and HuH7 in vitro. The drug combination solicited a higher percentage of apoptosis cells and induced higher levels of cleaved caspase-9, -3, and PARP than temsirolimus or adriamycin used alone. The ratio of Bax/Bcl-2 was increased in cells exposed to the combination treatment. The enhanced anti-tumor effect of this drug combination was verified in a nude mice model. We also observed that half doses of temsirolimus and adriamycin used in combination achieved a comparable tumor growth inhibitor rate with full dose of temsirolimus or adriamycin used alone.. Temsirolimus plus adriamycin exhibited an enhanced antitumor effect in HCC and this drug combination might have a potential value in treatment of HCC. Studies are warranted to comprehensively evaluate the efficacy and safety of this regimen in the future.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Humans; Liver Neoplasms; Mice; Mice, Nude; Poly(ADP-ribose) Polymerases; Sirolimus; TOR Serine-Threonine Kinases

Globally, renal cell carcinomas (RCCs) represent a major portion of patients suffering from cancer. Temsirolimus is an anti-renal cancer drug that has already been approved in poor-risk metastatic RCC (mRCC) patients. In our present study, we have evaluated the in vitro effect of varying concentrations of temsirolimus on cancerous rat kidney cystatin; renal cancer was induced in rats making use of dimethylnitrosamine (DMN). It has already been reported that cancerous rat kidney cystatin performs its activity in an efficacious manner as compared to normal rat kidney cystatin, so here an attempt was made to see the effect of temsirolimus on this increased activity of cystatin in renal cancers. Anti-papain activity assay was utilized to see this effect and it was found that temsirolimus reduces the increased activity of cancerous rat kidney cystatin similar to that of normal rat kidney cystatin. Further, to have an insight into temsirolimus induced structural alterations in cancerous rat kidney cystatin; various spectroscopic assays viz. UV, Fluorescence, Circular dichroism (CD) and FTIR spectroscopy were employed. UV and Fluorescence spectroscopy shows cancerous rat kidney cystatin transformation to normal form in the presence of temsirolimus. FTIR and CD spectroscopy confirmed the complete structural reversion of cancerous rat kidney cystatin to normal form in the presence of 40μM temsirolimus. Thus, it can said that temsirolimus causes renal cystatin to revert to normal form; the increased activity of renal cystatin observed in incidences of renal cancer is restored back to normal thereby halting the progression of renal cancer.

Topics: Animals; Cystatins; Kidney; Kidney Neoplasms; Male; Papain; Rats; Sirolimus

Topics: Aged; Antineoplastic Agents; Calcinosis; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Palliative Care; Protein Kinase Inhibitors; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

Metabolic toxicities of mTOR inhibitors (mTORi) are well characterized. The purpose of the study was to investigate the relationship between these metabolic toxicities and mTORi efficacy.. From 2007 to 2011, metabolic toxicities were retrospectively collected in patients treated with an mTORi (everolimus, temsirolimus) for a metastatic renal cell carcinoma (mRCC) in a single institution. Patients were eligible if they have received an mTORi for at least 28 days. Changes in the following parameters were analyzed: lymphocytes, serum creatinine, glycemia, serum phosphate, liver transaminases, cholesterol, and triglycerides. The efficacy was assessed by progression-free survival (PFS) and tumor response.. Data were collected from seventy-five patients (everolimus = 44 patients; temsirolimus = 31 patients). Six patients exhibited a partial response, 42 a stable disease and 15 had a progressive disease (12 missing). After a median follow-up of 12.8 months, the median PFS was 6.7 months (95% confidence interval: 4.0-9.1 months). Patients with CB had a statistically more severe absolute increase of glycemia and absolute decrease in phosphatemia (p = 0.002 and p = 0.02 respectively). The Progression Free Survival was significantly higher with the onset rate of hypophosphatemia (p = 0.03) and hyperglycemia (p = 0.001) and lower with the onset rate of lymphopenia (p = 0.004).. Hyperglycemia, hypophosphatemia and lymphopenia, were significantly associated with tumor response and/or PFS. Those events, as well as their onset rate, should be prospectively monitored as predictors of response to mTORi.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Biomarkers, Tumor; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; France; Humans; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Renal cell carcinoma (RCC) is one of the most common neoplasms that occurs in the kidney and is marked by a unique biology, with a long history of poor response to conventional cancer treatments. In recent years, there have been significant advancements implemented to understanding the biology of RCC, which has led to the introduction of novel targeted therapies in the management of patients with metastatic disease.. The present study was designed to evaluate the effects of p38 MAPK inhibitor (SB203580), alone and in combination with mTOR inhibitor (CCI779) on apoptosis and cell proliferation.. Subtoxic concentrations of inhibitors were selected by MTT assay using A-498, ACHN and primary culture of RCC.. All the three types of RCC cells had almost similar response towards these inhibitors. The results revealed that 25µM of SB203580 and 20µM of CCI779 at 48 hrs decreased cell viability by 20% and 30%, respectively, whereas the combination of both inhibitors showed a maximum of 40% reduction in cell viability.. The study concludes that the combination of SB203580 and CCI779 inhibitors may induce cellular senescence in A-498 cells with higher potency than that of individual inhibitors.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Imidazoles; Kidney Neoplasms; Molecular Structure; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyridines; Sirolimus; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Tumor Suppressor Protein p53

The mammalian target of rapamycin (mTOR) is commonly activated in colon cancer. mTOR complex 1 (mTORC1) is a major downstream target of the PI3K/ATK pathway and activates protein synthesis by phosphorylating key regulators of messenger RNA translation and ribosome synthesis. Rapamycin analogs Everolimus and Temsirolimus are non-ATP-competitive mTORC1 inhibitors, and suppress proliferation and tumor angiogenesis and invasion. We now show that apoptosis plays a key role in their anti-tumor activities in colon cancer cells and xenografts through the DR5, FADD and caspase-8 axis, and is strongly enhanced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and 5-fluorouracil. The induction of DR5 by rapalogs is mediated by the ER stress regulator and transcription factor CHOP, but not the tumor suppressor p53, on rapid and sustained inhibition of 4E-BP1 phosphorylation, and attenuated by eIF4E expression. ATP-competitive mTOR/PI3K inhibitors also promote DR5 induction and FADD-dependent apoptosis in colon cancer cells. These results establish activation of ER stress and the death receptor pathway as a novel anticancer mechanism of mTOR inhibitors.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Colonic Neoplasms; Everolimus; Female; Humans; Mice, Nude; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Receptors, TNF-Related Apoptosis-Inducing Ligand; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factor CHOP; Xenograft Model Antitumor Assays

Autophagy enables cells to digest endogenous/exogenous waste products, thus potentially prolonging the cellular lifespan. Early endothelial progenitor cells (eEPCs) protect mice from ischemic acute kidney injury (AKI). The mid-term prognosis in AKI critically depends on vascular rarefication and interstitial fibrosis with the latter partly being induced by mesenchymal transdifferentiation of endothelial cells (EndoMT). This study aimed to determine the impact of eEPC preconditioning with different autophagy inducing agents [suberoylanilide hydroxamic acid (SAHA)/temsirolimus] in ischemic AKI.. Male C57/Bl6 N mice were subjected to bilateral renal ischemia (40 min). Animals were injected with either untreated, or SAHA- or temsirolimus-pretreated syngeneic murine eEPCs at the time of reperfusion. Mice were analyzed 48 h and 4 weeks later. In addition, cultured eEPCs were treated with transforming growth factor (TGF)-β ± SAHA, autophagy (perinuclear LC3-II), and stress-induced premature senescence (SIPS-senescence-associated β-galactosidase, SA-β-Gal), and were evaluated 96 h later.. Cultured eEPCs showed reduced perinuclear density of LC3-II + vesicles and elevated levels of SA-β-Gal after treatment with TGF-β alone, indicating impaired autophagy and aggravated SIPS. These effects were completely abrogated by SAHA. Systemic administration of either SAHA or tems pretreated eEPCs resulted in elevated intrarenal endothelial p62 at 48 h and 4 weeks, indicating stimulated endothelial autophagy. This effect was most pronounced after injection of SAHA-treated eEPCs. At 4 weeks endothelial expression of mesenchymal alpha-smooth muscle actin (αSMA) was reduced in animals receiving untreated and SAHA-pretreated cells. In addition, SAHA-treated cells reduced fibrosis at week 4. Tems in contrast aggravated EndoMT. Postischemic renal function declined after renal ischemia and remained unaffected in all experimental cell treatment groups.. In ischemic AKI, intrarenal endothelial autophagy may be stabilized by systemic administration of pharmacologically preconditioned eEPCs. Early EPCs can reduce postischemic EndoMT and fibrosis in the mid-term. Autophagy induction in eEPCs either increases or decreases the mesenchymal properties of intrarenal endothelial cells, depending on the substance being used. Thus, endothelial autophagy induction in ischemic AKI, mediated by eEPCs is not a renoprotective event per se.

Topics: Actins; Acute Kidney Injury; Animals; Autophagy; beta-Galactosidase; Cells, Cultured; Disease Models, Animal; Endothelial Progenitor Cells; Epithelial-Mesenchymal Transition; Fibrosis; Hydroxamic Acids; Ischemia; Kidney; Male; Mice, Inbred C57BL; Microtubule-Associated Proteins; Phenotype; Sirolimus; Time Factors; Transforming Growth Factor beta; Vorinostat

To assess the prognostic value of clinical and biological features in patients treated with second-line targeted therapies (TT) for a metastatic renal cell carcinoma (mRCC).. A retrospective study was performed including 60 patients treated with second-line TT from 2006 to 2013. Clinical and biological features were collected, including TT-induced toxicities, Heng and MSKCC prognostic scores, and renal function. Overall survival (OS) and progression-free survival (PFS) were assessed using univariate and multivariate analysis.. The median age was 61 years [39-81]. MSKCC and Heng scores were significantly prognostic for OS and PFS (P<0.05). Hypo-albuminemia, anemia and brain metastasis were associated with poorer OS and PFS (P<0.05). Severe induced toxicities had a prognostic impact with higher OS (26 months vs 10 months, P=0.003) and PFS (5 months vs 4 months, P=0.047). Renal function impairment at the initiation of the second line was also associated with higher survival (OS=24 months vs 9 months, P=0.035 and PFS=7 months vs 4 months, P=0.043). On multivariate analysis, induced toxicity was found as an independent factor of good prognosis for OS (HR=0.36; P=0.01).. Our results suggested that renal function impairment and TT-induced toxicities in the second line of treatment for mRCC have a potential prognostic interest as it had previously been reported for the first line of TT.. 5.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Prognosis; Pyrroles; Retrospective Studies; Risk Factors; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA-approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.

Topics: Animals; Blood Glucose; Cell Proliferation; Glucose Intolerance; Homeostasis; Immune System; Insulin-Secreting Cells; Mice, Inbred C57BL; Signal Transduction; Sirolimus

Recent preclinical and clinical studies on head and neck squamous cell carcinoma (HNSCC) revealed synergistic effects when combining anti-EGFR agents with conventional chemotherapeutic drugs. Activation of the PI3-kinase/AKT/mTOR signaling pathway has been identified as an important mechanism implicated in tumor progression and resistance to EGFR inhibitors. The aim of this study was to investigate the effects of combining the mTOR inhibitor temsirolimus (Tem) with the anti-EGFR agent cetuximab (Cet) and conventional chemotherapeutic drugs (cisplatin and fluorouracil (C/F)) on an orthotopic model of HNSCC.. Preclinical in vivo study.. We evaluated the anti-tumor efficacy (measured tumor volume) of Tem, Cet, and C/F, administered alone or in combination. Investigations were performed using a human HNSCC cell line, CAL33, injected into the mouth floor of nude mice.. As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced almost complete tumor growth arrest (P = 0.001). Tem significantly enhanced the impact of the Cet-C/F combination on tumor growth (P < 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labeling), MAPK (pP42/44 labeling), and PI3K/AKT/mTOR (pS6R labeling) signaling pathways were found with the Tem-Cet association.. In this orthotopic HNSCC model, the combination of Tem with Cet produced synergistic effects on tumor growth. These results were corroborated by a strong inhibition of both MAPK and PI3K-mTOR signaling pathways.. N/A.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Line, Tumor; Cetuximab; Cisplatin; ErbB Receptors; Fluorouracil; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

A major pathological hallmark in several neurodegenerative disorders, like polyglutamine disorders (polyQ), including Machado-Joseph disease (MJD), is the formation of protein aggregates. MJD is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormal protein, which is prone to misfolding and forms cytoplasmic and nuclear aggregates within neurons, ultimately inducing neurodegeneration. Treatment of proteinopathies with drugs that up-regulate autophagy has shown promising results in models of polyQ diseases. Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (m-TOR), while lithium chloride (LiCl) acts by inhibiting inositol monophosphatase, both being able to induce autophagy. We have previously shown that chronic treatment with LiCl (10.4 mg/kg) had limited effects in a transgenic MJD mouse model. Also, others have shown that CCI-779 had mild positive effects in a different mouse model of the disease. It has been suggested that the combination of mTOR-dependent and -independent autophagy inducers could be a more effective therapeutic approach. To further explore this avenue toward therapy, we treated CMVMJD135 transgenic mice with a conjugation of CCI-779 and LiCl, both at concentrations known to induce autophagy and not to be toxic. Surprisingly, this combined treatment proved to be deleterious to both wild-type (wt) and transgenic animals, failing to rescue their neurological symptoms and actually exerting neurotoxic effects. These results highlight the possible dangers of manipulating autophagy in the nervous system and suggest that a better understanding of the potential disruption in the autophagy pathway in MJD is required before successful long-term autophagy modulating therapies can be developed.

Topics: Animals; Animals, Genetically Modified; Ataxin-3; Autophagy; Brain; Caenorhabditis elegans; Central Nervous System Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Lithium Compounds; Locomotion; Machado-Joseph Disease; Male; Mice, Inbred C57BL; Motor Activity; Neurotoxicity Syndromes; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway. It plays a pivotal role in the control of cell proliferation, survival, and angiogenesis with multiple and frequent dysregulations of this pathway in human tumors. Temsirolimus is an intravenous drug, specifically inhibiting the mTOR pathway. Bendamustine is well known for its clinical activity in indolent non-Hodgkin-lymphoma (NHL) and has lately shown clinical activity in mantle cell lymphoma (MCL). Here, we present a case report of temsirolimus in combination with bendamustine and rituximab leading to a CR in a pretreated male. In addition, our in vitro data underlines the additive and synergistic efficacy in cell growth reduction of temsirolimus combined with bendamustine in MCL cell lines and in DLBCL cell lines. Furthermore, as an underlying mechanism of this additive, effects on cell cycle inhibition and apoptosis induction could be identified.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cell Line, Tumor; Drug Synergism; G1 Phase; Humans; Lymphoma, Mantle-Cell; Male; Rituximab; Sirolimus

Topics: Adenine; Antineoplastic Agents; Female; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Sirolimus

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the RAF/mitogen-activated and extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are frequently deregulated in cancer. Temsirolimus (TEM) and its primary active metabolite rapamycin allosterically block mTOR complex 1 substrate recruitment. The context-/experimental setup-dependent opposite effects of rapamycin on the multiple centrosome formation, aneuploidy, DNA damage/repair, proliferation, and invasion were reported. Similarly, the context-dependent either tumor-promoting or suppressing effects of RAF-MEK-ERK pathway and its inhibitors were demonstrated. Drug treatment-mediated stress may promote chromosomal instability (CIN), accelerating changes in the genomic landscape and phenotype diversity. Here, we characterized the genomic and phenotypic changes of U251 and T98G glioblastoma cell lines long-term treated with TEM or U0126, an inhibitor of MEK1/2. TEM significantly increased clonal and non-clonal chromosome aberrations. Both TEM and U0126 affected copy number alterations (CNAs) pattern. A proliferation rate of U251TEM and U251U0126 cells was lower and higher, respectively, than control cells. Colony formation efficiency of U251TEM significantly decreased, whereas U251U0126 did not change. U251TEM and U251U0126 cells decreased migration. In contrast, T98GTEM and T98GU0126 cells did not change proliferation, colony formation efficiency, and migration. Changes in the sensitivity of inhibitor-treated cells to the reduction of the glucose concentration were observed. Our results suggest that CIN and adaptive reprogramming of signal transduction pathways may be responsible for the cell type-dependent phenotype changes of long-term TEM- or U0126-treated tumor cells.

Topics: Butadienes; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromosomal Instability; Glioblastoma; Glucose; Humans; MAP Kinase Signaling System; Nitriles; Phenotype; Protein Kinase Inhibitors; Sirolimus

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms.

Topics: alpha-Fetoproteins; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Combinations; Everolimus; Extracellular Signal-Regulated MAP Kinases; G1 Phase Cell Cycle Checkpoints; Hep G2 Cells; Humans; Imidazoles; Insulin; Liver Neoplasms; Proto-Oncogene Proteins c-akt; Pyrazines; Receptor, IGF Type 1; Receptors, Somatomedin; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases

Everolimus is an approved agent for use after disease progression with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. With recently published trials showing efficacy of nivolumab and cabozantinib in the second-line therapy setting, the use of everolimus will likely move to the third- or fourth-line therapy setting. Temsirolimus has occasionally been used instead of everolimus for many reasons, including financial considerations, assurance of patient compliance given its intravenous administration, its toxicity profile, patient performance status, and patient or physician preference. However, efficacy of everolimus and temsirolimus in this setting have not been compared in a randomized trial. The results from retrospective studies have been inconsistent.. We identified patients treated with a first-line VEGFR-TKI for metastatic renal cell carcinoma and then treated with either everolimus or temsirolimus on progression from the databases of 2 large academic cancer centers. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of second-line treatment using the Kaplan-Meier method.. A total of 90 patients received either everolimus (n = 59; 66%) or temsirolimus (n = 31; 34%) after progression during first-line VEGFR-TKI therapy. The patient and disease characteristics were similar in both groups. The median PFS was not different, but OS was superior with everolimus compared with temsirolimus (24.2 months vs. 12.1 months; hazard ratio, 0.58; P = .047).. Our results bolster existing guidelines supporting everolimus over temsirolimus as salvage therapy after previous systemic therapies.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies; Salvage Therapy; Sirolimus; Survival Analysis; Treatment Outcome

Acquisition of mesenchymal properties by cancer cells is critical for their malignant behaviour, but regulators of the mesenchymal molecular machinery and how it is activated remain elusive. Here we show that clear cell renal cell carcinomas (ccRCCs) frequently utilize the Arf6-based mesenchymal pathway to promote invasion and metastasis, similar to breast cancers. In breast cancer cells, ligand-activated receptor tyrosine kinases employ GEP100 to activate Arf6, which then recruits AMAP1; and AMAP1 then binds to the mesenchymal-specific protein EPB41L5, which promotes epithelial-mesenchymal transition and focal adhesion dynamics. In renal cancer cells, lysophosphatidic acid (LPA) activates Arf6 via its G-protein-coupled receptors, in which GTP-Gα12 binds to EFA6. The Arf6-based pathway may also contribute to drug resistance. Our results identify a specific mesenchymal molecular machinery of primary ccRCCs, which is triggered by a product of autotaxin and it is associated with poor outcome of patients.

Topics: ADP-Ribosylation Factor 6; ADP-Ribosylation Factors; Adult; Aged; Aged, 80 and over; Amides; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Female; GTP-Binding Protein alpha Subunits, G12-G13; Guanine Nucleotide Exchange Factors; HEK293 Cells; Humans; Immunohistochemistry; Indoles; Isoxazoles; Kidney Neoplasms; Lysophospholipids; Male; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Nerve Tissue Proteins; Propionates; Pyridines; Pyrroles; Receptors, Lysophosphatidic Acid; Signal Transduction; Sirolimus; Sunitinib; Triazoles

We evaluated the efficacy and toxicity of mammalian target rapamycin inhibitors in Korean patients with metastatic renal cell carcinoma (mRCC) with chronic renal insufficiency not requiring dialysis.. Korean patients with mRCC and chronic renal insufficiency not requiring dialysis treated with everolimus or temsirolimus between January 2008 and December 2014 were included. Patient characteristics, clinical outcomes, and toxicities were evaluated. Overall survival (OS) and progression-free survival (PFS) durations were evaluated according to the degree of renal impairment.. Mammalian target rapamycin inhibitors were efficacious and did not increase toxicity in Korean patients with mRCC and chronic renal insufficiency not requiring dialysis.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Neoplasm Metastasis; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Aberrant epidermal growth factor receptor (EGFR) signaling is associated with tumor growth in head and neck squamous cell carcinoma (HNSCC) and is a major focus of targeted therapy. The phosphatidylinositol-3-kinase/AKT/mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway is frequently mutated in HNSCC and is involved in disease progression and resistance to EGFR inhibitors. The aim of this study was to assess the antiproliferative effects of mTOR inhibition (temsirolimus) combined with the anti-EGFR monoclonal antibody cetuximab, administered according to different combination schedules. Antiproliferative effects of the combination of temsirolimus and cetuximab were determined on the representative HNSCC CAL33 cell line (PI3KCA H1047R mutated and K-RAS wild-type). In addition, key proteins related to the EGFR pathway (pEGFR/EGFR, pAKT/AKT) and the mTOR pathway (p-p70S6K1, p4E-BP1) were determined to explain the cytotoxic effects. Temsirolimus and cetuximab showed a synergistic effect when administered in combination. Supra-additive effect was lost when the two drugs were administered sequentially, irrespective of which drug was administered first. Synergistic effect of the combination was corroborated by a marked downregulation of pEGFR, significant downregulation of pAKT expression, and a marked diminution of p70S6K1 and p4E-BP1 expression. Our study demonstrated a synergistic effect of temsirolimus and cetuximab administered in combination, well illustrated by a simultaneous blockade of intracellular signaling pathways regulating cell proliferation and survival. These results establish the notion of a schedule dependency for the combined treatment, which can be of importance at the clinical level.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Line, Tumor; Cetuximab; Drug Administration Schedule; Drug Interactions; Drug Synergism; ErbB Receptors; Head and Neck Neoplasms; Humans; Mechanistic Target of Rapamycin Complex 1; Proto-Oncogene Proteins c-akt; ras Proteins; Sirolimus; Squamous Cell Carcinoma of Head and Neck

Topics: Adenine; Antineoplastic Agents; Bendamustine Hydrochloride; Bortezomib; Chromosomes, Human, Pair 17; Cytarabine; Humans; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Mutation; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Sirolimus; Thalidomide; Tumor Suppressor Protein p53; Vidarabine

It has been proposed that resistance to rapalog therapies in renal cell carcinoma (RCC) is due to adaptive switching from mammalian target of rapamycin complex 1 (mTORC1) to mTORC2.. To combine phosphoprotein staining and applied biomedical analytics to investigate resistance signatures in patients with metastatic RCC progressing on rapalog therapies.. We applied morphoproteomic analysis to biopsy specimens from nine patients with metastatic RCC who continued to show clinical progression of their tumors while being treated with a rapalog.. In patients who were on temsirolimus or everolimus at the time of biopsy, a moderate to strong expression of phosphorylated (p)-mTOR (Ser 2448) in the nuclear compartment with concomitant expression of p-Akt (Ser 473) confirmed the mTORC2 pathway. Concomitant moderate to strong nuclear expression of p-ERK 1/2 (Thr202/Tyr204) and p-STAT3 (Tyr705) was confirmed. Histopathologic changes of hypoxic-type coagulative necrosis in 5 cases as well as identification of insulin-like growth factor-1 receptor (IGF-1R) expression and histone methyltransferase EZH2 in all tumors studied suggested that hypoxia also contributed to the resistance signature. Biomedical analytics provided insight into therapeutic options that could target such adaptive and pathogenetic mechanisms.. Morphoproteomics and biomedical analytics confirm mTORC2/Akt as a resistance signature to rapalog therapy in metastatic RCC and demonstrate activation of the prosurvival ERK and STAT3 pathways and involvement of hypoxic pathways that contribute to pathogenesis of such adaptive resistance. These results highlight the need for a novel combinatorial therapeutic approach in metastatic RCC progressing on rapalogs.

Topics: Apoptosis; Carcinoma, Renal Cell; Cell Size; Cell Survival; Computational Biology; Disease Progression; Drug Resistance, Neoplasm; Enzyme Activation; Everolimus; Extracellular Signal-Regulated MAP Kinases; Gene Expression Profiling; Humans; Kidney Neoplasms; MAP Kinase Signaling System; Mechanistic Target of Rapamycin Complex 2; Neoplasm Metastasis; Oncogene Protein v-akt; Proteomics; Signal Transduction; Sirolimus; STAT3 Transcription Factor; Tumor Burden

The predictive role of objective remission remains undefined for targeted agents in metastatic renal cell carcinoma (mRCC); however, early tumour shrinkage (eTS) was shown to be predictive and/or prognostic for overall survival (OS) and progression-free survival (PFS) in mRCC in several small studies.. To evaluate the degree of eTS following systemic therapy that may predict survival in mRCC.. Data from 4334 patients with mRCC in phase 2 and 3 clinical trials between 2003 and 2013 were pooled for analyses. Early tumour shrinkage was assessed based on percentage change in sum of the longest diameters of target lesions at first postbaseline scan. Patients were categorised by a more or equal versus less optimal threshold of eTS, assessed using receiver operating characteristic (ROC) analysis. OS and PFS in patients with eTS were summarised using the Kaplan-Meier method.. Axitinib, bevacizumab, interferon α, sorafenib, sunitinib, or temsirolimus.. We measured optimal thresholds of eTS and eTS as a predictor of OS or PFS.. Optimal threshold of eTS for the prediction of OS and PFS was determined to be approximately 10%. In Cox proportional hazards models, compared with patients without eTS, those with eTS had significantly longer OS (hazard ratio [HR]: 0.615; p<0.0001; median: 28.5 vs 16.0 mo) and PFS (HR: 0.628; p<0.0001; median: 10.5 vs 5.3 mo). The major limitation was the retrospective nature of our analysis, including different lines and types of therapy, although subset analyses detected a similar predictive pattern for eTS across all lines and types of therapy.. Early tumour shrinkage ≥10% at first postbaseline assessment could serve as a putative early end point in patients with mRCC. A prospective evaluation of eTS in clinical trials is warranted.. Early tumour shrinkage may be used to identify patients with metastatic renal cell carcinoma who would benefit from treatment with antitumour agents.. The clinical trials are registered on ClinicalTrials.gov (NCT00267748, NCT00338884, NCT00835978, NCT00065468, NCT00083889, NCT00631371, NCT00920816, NCT00077974, NCT00137423, NCT00054886, NCT00678392, and NCT00474786).

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Bone Neoplasms; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prognosis; Proportional Hazards Models; Pyrroles; Remission Induction; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate; Treatment Outcome; Tumor Burden

Metastatic renal cell carcinoma (mRCC) has historically been refractory to cytotoxic and hormonal agents. IL-2 and IFN-α provide response in a minority of patients. Small molecule tyrosine kinase inhibitors and monoclonal antibodies have established a role in the setting of mRCC. However, there is a lack of data from the Indian subcontinent. The aim of this study was to look whether our patients behave similarly as reported in the Western data to targeted agents, especially sunitinib.. The study was a prospective observational study conducted for a period of 5 years from 2011 to 2016. Sixty-three patients received targeted agents and were recruited in the study. Five patients were excluded for various reasons, and three were lost to follow-up. Fifty-five patients were properly studied and followed up. Fifty patients received sunitinib, four patients received sorafenib, and one patient received parenteral temsirolimus. Patients were followed for AEs and survival.. The most common AEs in patients taking sunitinib were fatigue (70 %), hand-foot syndrome (62 %), skin rash (58 %), mucosal inflammation (58 %), anorexia (42 %), skin discoloration (42 %), followed by dry mouth, dysgeusia, dyspepsia, dry skin, dry mouth, hair color changes, hypothyroidism, alopecia, oral pain/stomatitis, hypertension, decreased weight, photosensitivity, peripheral edema, erythema, and others. The median overall survival in our patients was 13.2 (95 % CI 10.1-16.5), progression-free survival was 8.1 months (95 % CI 6.4-10.5), and objective response was seen in 36 %.. Non-Western patients behave differently with sunitinib therapy compared to Western patients. Our patients have more mucocutaneous side effects and lesser overall survival.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Agents; Carcinoma, Renal Cell; Developing Countries; Disease-Free Survival; Fatigue; Female; Follow-Up Studies; Hand-Foot Syndrome; Humans; India; Indoles; Kidney Neoplasms; Male; Middle Aged; Mucositis; Niacinamide; Phenylurea Compounds; Pigmentation Disorders; Prospective Studies; Pyrroles; Response Evaluation Criteria in Solid Tumors; Sirolimus; Sorafenib; Sunitinib; Survival Rate; White People; Young Adult

To identify predictors of prolonged or shortened progression-free survival (PFS) and overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) who received first-line targeted therapies.. This retrospective study included 146 patients with mRCC who were treated during 2007-2015. These patients were divided into a group with the worst response (WG), an expected group (EG), and a group with the best response (BG), based on their PFS (≤3 monthsnths, 3-18 monthsnths, and >18 monthsnths, respectively) and OS (<1 year, 1-3 years, and >3 years, respectively). To identify significant predictive factors, the BG and WG were compared to the EG using the Memorial Sloan Kettering Cancer Center and Heng risk models.. The overall PFS and OS were 9.3 months and 16.4 months, respectively. The median PFS for the WG (41.8 %), EG (45.9 %), and BG (12.3 %) were 2.7 months, 9.3 months, and 56.6 months, respectively, and the median OS for the WG (45.9 %), EG (35.6 %), and BG (18.5 %) were 5.5 months, 21.6 months, and 63.1 months, respectively; these outcomes were significantly different (p < 0.001). Nephrectomy (odds ratio [OR]: 7.15) was a significant predictor of PFS in the BG, and the significant predictors of OS in the BG were MSKCC intermediate risk (OR: 0.12), poor risk (OR: 0.04), and a disease-free interval of <1 year (OR: 0.23) (all, p < 0.05). Anemia (OR: 3.25) was a significant predictor of PFS in the WG, and the significant predictors of OS were age (OR: 1.05), anemia (OR: 4.13), lymphocytopenia (OR: 4.76), disease-free interval of <1 year (OR: 4.8), and synchronous metastasis (OR: 3.52) (all, p < 0.05).. We identified several significant predictors of unexpectedly good and poor response to first-line targeted therapy among patients with mRCC.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome

Metastatic renal cell carcinoma (mRCC) develops in approximately 33% of all renal cancer patients. First line treatment of mRCC includes drugs such as sunitinib, temsirolimus and pazopanib, with overall survival now reaching up to 43,6months in patients with favorable-risk metastatic disease. Several side-effects in mRCC treatment, such as hypothyroidism, can be used as positive prognostic factors and indicate good response to therapy. Hypercholesterolemia and hypertriglyceridemia independent of hypothyroidism are reported as side-effects in temsirolimus treatment and recently in sunitinib treatment, but the exact mechanism and significance of the changes remains elusive. Most likely, metabolic changes are caused by inhibition of mechanistic target of rapamycin (mTOR), a positive target of tumor growth suppression, but also a regulator of iron homeostasis. There are no clinical studies reporting changes in iron and ferritin levels during mRCC biotherapy, but we hypothesize that inhibition of mTOR will also affect iron and ferritin levels. If both lipid and iron changes correlate, there is a high possibility that both changes are primarily caused by mTOR inhibition and the level of change should correlate with the inhibition of mTOR pathway and hence the efficacy of targeted treatment. We lastly hypothesize that mRCC biotherapy causes hypercholesterolemia with a possibly improved cholesterol profile due to increase HDL/LDL ratio, so statins might not have a role as supplementary treatment, whereas a sharp rise in triglyceride levels seems to be the primary target for additional therapy.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Cholesterol; Ferritins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertriglyceridemia; Hypothyroidism; Indazoles; Indoles; Iron; Kidney Neoplasms; Lipids; Metabolome; Models, Theoretical; Neoplasm Metastasis; Prognosis; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Triglycerides

Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxyglucose; Female; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Male; NADP; Neoplasm Proteins; Neoplastic Stem Cells; NF-E2-Related Factor 2; Sesquiterpenes; Sirolimus; Up-Regulation

Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that is a central regulator of cell growth and metabolism. CCI-779 is a specific inhibitor of the mTORC1 signaling pathway.. We performed comparative transcriptome profiling on Inner Mongolia Cashmere goat fetal fibroblasts (GFbs) that were treated with CCI-779 and untreated cells. A total of 365 differentially expressed genes (DEGs) appeared between untreated and CCI-779-treated GFbs, with an FDR ≤0.001 and fold-change ≥2. These 365 DEGs were associated with mTOR signaling; 144 were upregulated in CCI-779-treated cells, and 221 were downregulated. Additionally, 300 genes were annotated with 43 Gene Ontology (GO) terms, and 293 genes were annotated with 194 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Three RNA polymerase II and polymerase III subunits, 3 transcription factors, and 5 kinases in mTOR signaling were differentially expressed in CCI-779-treated GFbs. Further 6 DEGs were related to amino acid metabolism, 11 mediated lipid metabolism, 11 participated in carbohydrate metabolism, and 5 were involved in single-nucleotide metabolism. Based on our quantitative transcriptomic analysis, 40 significant DEGs with important function related to metabolism, RNA polymerase, transcription factors and mTOR signaling were selected for qPCR analysis, and the quantitative results between the two analysis methods were concordant. The qPCR data confirmed the differential expression in the RNA-Seq experiments. To validate the translational significance of the findings in certain differentially expressed genes, S6K1 and VEGF were detected by western blot, and these two proteins showed a differential expression between non-treated and treated with CCI-779 groups, which were consistent with mRNA abundance. The data showed a preliminary significance of the findings in the protein levels.. CCI-779 induces transcriptomic changes, and mTOR signaling might have significant function in the activation of RNA polymerase and certain transcription factors and in the metabolism of amino acids, lipids, carbohydrates, and single nucleotides in GFbs. These data filled the vacancy in the systematical profiling of mTOR signaling on Cashmere goat fetal fibroblasts.

Topics: Amino Acids; Animals; Carbohydrate Metabolism; Cluster Analysis; Computational Biology; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation; Goats; High-Throughput Nucleotide Sequencing; Lipid Metabolism; Metabolic Networks and Pathways; Models, Biological; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors; Transcriptome

Hutchinson-Gilford syndrome (HGPS, OMIM 176670, a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Lamins help maintain the shape and stability of the nuclear envelope in addition to regulating DNA replication, DNA transcription, proliferation and differentiation. The LMNA mutation results in the deletion of 50 amino acids from the carboxy-terminal region of prelamin A, producing the truncated, farnesylated protein progerin. The accumulation of progerin in HGPS nuclei causes numerous morphological and functional changes that lead to premature cellular senescence. Attempts to reverse this HGPS phenotype have identified rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), as a drug that is able to rescue the HGPS cellular phenotype by promoting autophagy and reducing progerin accumulation. Rapamycin is an obvious candidate for the treatment of HGPS disease but is difficult to utilize clinically. To further assess rapamycin's efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage, we tested temsirolimus, a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin. We report that temsirolimus decreases progerin levels, increases proliferation, reduces misshapen nuclei, and partially ameliorates DNA damage, but does not improve proteasome activity or mitochondrial dysfunction. Our findings suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells.

Topics: Autophagy; Cell Nucleus; Cell Proliferation; DNA Damage; Fibroblasts; Homeostasis; Humans; Lamin Type A; Mitochondria; Phenotype; Progeria; Sirolimus; Superoxides

There have been few reports of the differences in safety between the mammalian target of rapamycin inhibitors, everolimus and temsirolimus. The purpose of this study is to compare the adverse event profiles of both agents and to estimate the risk factors for non-infectious pneumonitis in patients with advanced renal cell carcinoma on the basis of our real-world clinical experience.. Data from 218 consecutive patients that received either everolimus or temsirolimus for advanced renal cell carcinoma at five Japanese centers were retrospectively analyzed. Chi-squared test and univariate and multivariate logistic regression analyses were performed to investigate the differences in adverse event profiles and the risk factors associated with non-infectious pneumonitis, respectively.. A total of 196 patients were evaluable. In the everolimus group compared with temsirolimus, stomatitis (56 vs 30 %, p < 0.001) and non-infectious pneumonitis (38 vs 22 %, p = 0.018) were more frequently observed, and asthenia (11 vs 23 %, p = 0.027), rash (20 vs 36 %, p = 0.018), and fatigue (33 vs 48 %, p = 0.032) occurred less frequently in all grades. On multivariate analysis, male gender (odds ratio 3.65; 95 % confidence interval 1.44-9.26, p = 0.007) and everolimus treatment (odds ratio 2.00; 95 % confidence interval 1.01-3.96, p = 0.046) were significantly associated with development of non-infectious pneumonitis.. Our findings suggest that adverse event profiles may differ between everolimus and temsirolimus and that non-infectious pneumonitis may occur more frequently in patients treated with everolimus than temsirolimus. Further investigations are needed to confirm these results.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Pneumonia; Protein Kinase Inhibitors; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

Neurofibrillary tangles are intracellular inclusions made of tau protein that accumulates in neurons in Alzheimer's disease (AD) and in other tauopathies. We have investigated the ability of the rapamycin ester CCI-779/Temsilorimus, a mTOR inhibitor with better stability and pharmacological properties compared to rapamycin, to interfere with the development of a motor phenotype and tau pathology in a mutant tau mouse model developing neurofibrillary tangles, by stimulation of mTOR dependent macroautophagy. Mutant tau mice (Tg30) were treated with CCI-779 before onset of motor signs for 7 months (from 5 to 12 months of age) or after the onset of motor signs for 2 months (from 10 to 12 months of age). End-point motor deficits were 50% lower in the group of Tg30 mice treated for 7 months. Inhibition of mTOR signaling and stimulation of macroautophagy in the brain of CCI-779 treated Tg30 mice was suggested by decreased phosphorylation of mTOR downstream signaling molecules p70S6 kinase and Akt and increased level of the autophagy markers Rab7 and LC3-II. CCI-779 treatment decreased the brain levels of Sarkosyl-insoluble tau and phosphotau inTg30 mice both after 2 months or 7 months of treatment. The density of neurofibrillary tangles was significantly decreased when treatment was started prior onset of motor signs. These results indicate that stimulation of mTOR dependent autophagy by CCI-779 compound is efficient to counteract the accumulation of abnormal tau when administered early or late in a tauopathy model and to improve a motor deficit when started before onset of motor signs.

Topics: Analysis of Variance; Animals; Brain; Gene Expression Regulation; Humans; Liver; Mice; Mice, Transgenic; Motor Activity; Movement Disorders; Mutation; Protein Kinase Inhibitors; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins; Rotarod Performance Test; Signal Transduction; Sirolimus; tau Proteins; Tauopathies; TOR Serine-Threonine Kinases

Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that functions via two multiprotein complexes, namely mTORC1 and mTORC2, each characterized by different binding partners that confer separate functions. mTORC1 function is tightly regulated by PI3-K/Akt and is sensitive to rapamycin. mTORC2 is sensitive to growth factors, not nutrients, and is associated with rapamycin-insensitivity. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is thought to modulate growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases such as Akt and SGK. Recent evidence has suggested that mTORC2 may play an important role in maintenance of normal as well as cancer cells by virtue of its association with ribosomes, which may be involved in metabolic regulation of the cell. Rapamycin (sirolimus) and its analogs known as rapalogues, such as RAD001 (everolimus) and CCI-779 (temsirolimus), suppress mTOR activity through an allosteric mechanism that acts at a distance from the ATP-catalytic binding site, and are considered incomplete inhibitors. Moreover, these compounds suppress mTORC1-mediated S6K activation, thereby blocking a negative feedback loop, leading to activation of mitogenic pathways promoting cell survival and growth. Consequently, mTOR is a suitable target of therapy in cancer treatments. However, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. In recent years, new pharmacologic agents have been developed which can inhibit these complexes via ATP-binding mechanism, or dual inhibition of the canonical PI3-K/Akt/mTOR signaling pathway. These compounds include WYE-354, KU-003679, PI-103, Torin1, and Torin2, which can target both complexes or serve as a dual inhibitor for PI3-K/mTOR. This investigation describes the mechanism of action of pharmacological agents that effectively target mTORC1 and mTORC2 resulting in suppression of growth, proliferation, and migration of tumor and cancer stem cells.

Topics: Allosteric Regulation; Antibiotics, Antineoplastic; Catalytic Domain; Cell Line, Tumor; Cell Movement; Cell Survival; Everolimus; Glioblastoma; Humans; Immunosuppressive Agents; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mitosis; Multiprotein Complexes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Notch signaling is altered in many cancers. Our previous findings in primary pediatric ependymoma support a role for NOTCH in glial oncogenesis. The present study evaluates the γ-secretase inhibitor RO4929097 in glial tumor models. The expression of Notch pathway genes was evaluated using real-time RT-PCR in 21 ependymoma and glioma models. NOTCH1 mutations were analyzed by DNA sequencing. RO4929097 activity was evaluated in vitro and in vivo, as a single agent and in combination, in glioma and ependymoma models. Notch pathway genes are overexpressed in ependymomas and gliomas along with FBXW7 downregulation. NOTCH1 mutations in the TAD domain were observed in 20% (2/10) of ependymoma primary cultures. Blocking the Notch pathway with the γ-secretase inhibitor RO4929097 reduced cell density and viability in ependymoma short-term cultures. When combined with chemotherapeutic agents, RO4929097 enhanced temozolomide effects in ependymoma short-term cultures and potentiated the cytotoxicity of etoposide, cisplatinum, and temozolomide in glioma cells. RO4929097, in combined treatment with mTOR inhibition, potentiated cytotoxicity in vitro, but did not enhance antitumor effects in vivo. In contrast, RO4929097 enhanced irradiation effects in glioma and ependymoma xenografts and showed tumor growth inhibition in advanced-stage IGRG121 glioblastoma xenografts. RO4929097-mediated effects were independent of NOTCH1 mutation status or expression levels, but associated with low IL-6 levels. In established glial tumor models, NOTCH inhibition had limited effects as a single agent, but enhanced efficacy when combined with DNA-interfering agents. These preclinical data need to be considered for further clinical development of NOTCH inhibitors in glial tumors.

Topics: Amyloid Precursor Protein Secretases; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzazepines; Cell Line, Tumor; Cell Survival; Ependymoma; Gene Expression Regulation, Neoplastic; Glioma; Humans; Interleukin-6; Mice, Nude; Molecular Targeted Therapy; Protein Kinase Inhibitors; Receptor, Notch1; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Clinical trials have demonstrated that pazopanib prolongs progression-free survival (PFS), with an acceptable safety profile, for patients with advanced renal cell carcinoma (aRCC). The efficacy of second-line mammalian target of rapamycin (mTOR) inhibitors in pazopanib-treated patients has also been evaluated in clinical trials; however, few studies have evaluated first-line pazopanib or second-line mTOR inhibitors in real-world settings. The present study evaluated the outcomes of first-line pazopanib, and pazopanib followed by mTOR inhibitors, in a community oncology setting.. The present study was a retrospective analysis of eligible patients in US Oncology's iKnowMed electronic health records database who had been treated for aRCC from November 1, 2009 to August 31, 2012. The patients received first-line therapy with pazopanib (cohort 1), followed by second-line therapy with either everolimus or temsirolimus (cohort 2). The key outcomes included overall survival (OS), PFS, adverse events (AEs), treatment patterns, and healthcare resource use.. The median OS in cohort 1 (n = 177) was 22 months, and the median PFS was 8.5 months. The most common AEs were fatigue (56%), diarrhea (52%), vomiting (44%), and nausea (40%). The median persistence was 151 days with pazopanib. The median OS in cohort 2 (n = 35) was 16 months; the median PFS was 5.7 months. The most common AEs were fatigue (51%) and nausea (34%). The median persistence was 93 days with everolimus and 49 days with temsirolimus.. The outcomes for the patients treated with first-line pazopanib in the community setting were consistent with those reported by previous prospective and retrospective studies. Although the second-line cohort was small, the results of mTOR inhibitors after pazopanib were also consistent with those of previous observations.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Community Networks; Electronic Health Records; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Longitudinal Studies; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; United States; Young Adult

Limited data exist on the economic consequences of implementing targeted therapy (TT) for metastatic renal cell carcinoma (RCC) in a real-world setting.. To analyze health care and productivity costs for TT implementation in a national cohort of patients.. Costs were measured per patient per year during a 2-yr follow-up during 2002-2005 (immunotherapy only) and 2006-2009 (TT implementation). All Danish patients with a diagnosis code for RCC and a procedure code for TT or immunotherapy were linked to the Danish National Patient Registry (contains information on all contacts with primary and secondary health sector). Health care and productivity costs were retrieved from the Danish case-mix system and Coherent Social Statistics, respectively. Drug costs were calculated separately from procedure codes and retail prices.. Generalized linear models were used to analyze costs adjusted for age, gender, and civil status.. A total of 439 patients were included for 2006-2009 and 192 for 2002-2005. Comparison of the health care cost per patient per year between 2006-2009 and 2002-2005 revealed lower inpatient costs (€11 899 vs €19 944, adjusted relative risk [RR] 0.64), higher outpatient costs (€14 308 vs €6209, RR 2.39), lower radiotherapy costs (€194 vs €633, RR 0.31), higher radiology costs (€676 vs €191, RR 3.73), and higher separately calculated drug costs (€12 040 vs €3103, RR 3.82, all p<0.001) for the former. Total health care costs per patient per year did not significantly differ (€27 676 vs €27 856, RR 1.05, p=0.5) between the two periods. Income from employment did not significantly differ between 2006-2009 and 2002-2005 (RR 1.11, p=0.11) and costs associated with loss of productivity were €7852 and €8265, respectively.. A different pattern of health care costs were observed but total health care costs per patient per year did not significantly differ after implementation of TT for patients with mRCC.. In this nationwide study, we found changes in the pattern of health care costs for patients with metastatic kidney cancer after implementation of targeted therapy compared to an immunotherapy control period; however, total health care costs and income from employment were without significant changes.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Angiogenesis Inhibitors; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Costs and Cost Analysis; Denmark; Drug Costs; Efficiency; Employment; Everolimus; Female; Fluorouracil; Health Care Costs; Hospitalization; Humans; Immunologic Factors; Indoles; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrroles; Radiography; Radiotherapy; Registries; Sirolimus; Sorafenib; Sunitinib

Temsirolimus has shown efficacy as first-line treatment of patients with metastatic renal cell carcinoma and poor prognostic features. The efficacy of temsirolimus in other clinical settings, such as second-line therapy, is unclear. The aim of this study was to investigate the outcomes of an unselected group of patients with renal cancer treated with temsirolimus in a compassionate use program.. This retrospective analysis included all patients receiving temsirolimus at a tertiary referral center between November 2007 and October 2008. Information was obtained through review of patient notes, electronic records, and pharmacy records. Baseline characteristics, prognostic features, and previous treatments were recorded for all patients. Outcome measures were response rate, progression-free survival (PFS), overall survival (OS), and toxicities.. Thirty-eight patients were included in the analysis, with median age of 62 years, among whom 37% were untreated and 63% had received one or more previous treatments. Thirty-four percent of the patients had three or more poor prognostic factors. Four patients (11%) achieved a partial response (PR); in all four of these patients, the PR was confirmed by two subsequent computed tomography (CT) scans, and in one patient, the PR lasted for more than 18 months. A total of 34% achieved stable disease, and 50% had disease progression. Median OS was 7.6 months (95% confidence interval [CI] 4.8-10.5), and median PFS was 3.2 months (95% CI 1.0-5.5). Patients with two or fewer poor prognostic factors had a survival of 10.12 months compared with 5.03 months of those with three or more. Median survival was 14.9 months for untreated patients and 6.4 months for previously treated patients.. Our results indicate some efficacy of temsirolimus in untreated patients with renal tumors and poor-intermediate prognosis, although the limitations of small sample size and retrospective nature must be taken into account. The role of temsirolimus in previously treated patients remains controversial given the recently published results of the INTORSECT trial and the discrepancies between the few published series.

Topics: Administration, Intravenous; Antineoplastic Agents; Carcinoma, Renal Cell; Compassionate Use Trials; Dose-Response Relationship, Drug; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Prognosis; Retrospective Studies; Sirolimus; Survival Analysis; Tertiary Care Centers; Treatment Outcome

Topics: Aged; Bone Neoplasms; Carcinoma, Renal Cell; Disease Progression; Humans; Kidney Neoplasms; Male; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Portal branch ligation (PBL) can be performed before major hepatic resection of colorectal liver metastases (mCRC) to increase the remnant liver mass. However, PBL may also stimulate mCRC growth through hepatic arterial hyperperfusion and growth factor release. Herein, we studied whether hepatic arterial infusion (HAI) of the mTOR-inhibitor temsirolimus (Tem) is capable of inhibiting the growth of colorectal liver metastases after PBL. WAG/Rij rats were randomized to four groups (n=6 each) and underwent subcapsular implantation of 5×10(5) CC531 cells into the left liver lobe. The animals of two groups underwent simultaneous PBL of the tumour bearing liver lobe. Ten days later animals underwent a HAI either of temsirolimus (Tem and PBL Tem) or saline solution (Sham and PBL Sham). Tumour size was analyzed at days 10 and 13 using three-dimensional ultrasound. In Sham controls tumour volume increased by 43%. After PBL Sham tumour volume increased by 52%. In contrast, in animals undergoing HAI of temsirolimus the tumour growth was not only completely inhibited, but tumour volume was found decreased, irrespective of PBL. After HAI of temsirolimus immunohistochemistry revealed an increased cleaved caspase-3 activity, indicating stimulation of apoptotic cell death. In parallel temsirolimus treatment was associated with a significant reduction of PECAM-1 positive cells within the tumour tissue, implying a reduced tumour vascularisation. HAI of temsirolimus is capable of inhibiting the growth of CC531 colorectal rat liver metastases also after PBL.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Infusions, Intra-Arterial; Ligation; Liver; Liver Neoplasms; Male; Neoplasm Transplantation; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Portal Vein; Random Allocation; Rats; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden

The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era.. We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method.. A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFNα. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus.. In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice.

Topics: Adult; Aged; Angiotensins; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Female; Humans; Indoles; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Pyrroles; Renin-Angiotensin System; Sirolimus; Sunitinib; Treatment Outcome

Inhibitors of the mammalian target of rapamycin (mTORi) can produce de novo proteinuria in kidney transplant patients. On the other hand, mTORi has been shown to suppress disease progression in several animal models of kidney disease. In the present study, we investigated whether glomerular permeability can be acutely altered by the mTORi temsirolimus and whether mTORi can affect acute puromycin aminonucleoside (PAN) or angiotensin II (ANG II)-induced glomerular hyperpermeability. In anesthetized Wistar rats, the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Temsirolimus was administered as a single intravenous dose 30 min before the start of the experiments in animals infused with PAN or ANG II or in nonexposed animals. Polydispersed FITC-Ficoll-70/400 (molecular radius 10-80 Å) and (51)Cr-EDTA infusion was given during the whole experiment. Measurements of Ficoll in plasma and urine were performed sequentially before the temsirolimus injection (baseline) and at 5, 15, 30, 60, and 120 min after the start of the experiments. Urine and plasma samples were analyzed by high-performance size-exclusion chromatography (HPSEC) to assess glomerular sieving coefficients (θ) for Ficoll10-80Å. Temsirolimus per se increased baseline glomerular permeability to Ficoll50-80Å 45 min after its administration, a reactive oxygen species (ROS)-dependent phenomenon. PAN caused a rapid and reversible increase in glomerular permeability, peaking at 5 min, and again at 60-120 min, which could be blocked by the ROS scavenger tempol. mTORi abrogated the second permeability peak induced by PAN. However, it had no effect on the immediate ANG II- or PAN-induced increases in glomerular permeability.

Topics: Angiotensin II; Animals; Cell Membrane Permeability; Cyclic N-Oxides; Glomerular Filtration Rate; Kidney Glomerulus; Male; Models, Animal; Puromycin Aminonucleoside; Rats; Rats, Wistar; Sirolimus; Spin Labels; Time Factors; TOR Serine-Threonine Kinases

To assess the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) rechallenge for metastatic renal cell carcinoma (mRCC) patients and to identify predictive factors for increased progression-free survival (PFS) or overall survival (OS).. The clinicopathological features, outcomes, and prognostic factors of mRCC patients who were treated with VEGFR-TKI after treatment failure using both VEGFR-TKIs and mTOR inhibitors (mTORi) were reviewed.. A total of 29 eligible patients were included. Five (17 %) patients achieved partial response (PR) with a median response duration of 9.5 months (95 % CI 5.7-13.4 months), and additional 16 patients (55 %) achieved stable disease. With a median follow-up period of 19.2 months (95 % CI 18.9-19.6 months), the median PFS and OS were 3.0 months (95 % CI 1.1-4.9 months) and 4.9 months (95 % CI 2.9-6.8 months), respectively. In univariate analysis, the best response to first-line VEGFR-TKI (PR vs. non-PR, p < 0.001) and time to rechallenge (TTR, ≤12 months vs. between 12 and 24 months vs. >24 months, p = 0.005) were identified as predictive factors for longer PFS on VEGFR-TKI rechallenge. In addition, an MSKCC risk group (intermediate- vs. poor-risk group, p = 0.027), better response at first-line VEGFR-TKI (PR vs. non-PR, p = 0.003), and TTR (≤12 months vs. between 12 and 24 months vs. >24 months, p = 0.026) were identified as prognostic factors for longer OS.. VEGFR-TKI rechallenge may be a viable option for select metastatic RCC patients who fail both VEGFR-TKI and mTORi therapies.

Topics: Adult; Aged; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; DNA Mutational Analysis; Drug Substitution; Female; Genetic Predisposition to Disease; Humans; Kidney Neoplasms; Mutation; Phenotype; Protein Kinase Inhibitors; Sirolimus; Time Factors; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins

Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mTOR inhibitors, and evaluated the therapeutic activity of the survivin suppressant YM155 in RCC models. Here, we report that survivin expression levels were significantly higher in RCC cell lines compared with normal renal cells. Stable targeted knockdown of survivin completely abrogated the ability of 786-O RCC tumors to grow in mice, thus demonstrating its importance as a regulator of RCC tumorigenesis. We next explored multiple strategies to therapeutically inhibit survivin function in RCC. Treatment with the mTOR inhibitor temsirolimus partially diminished survivin levels and this effect was augmented by the addition of YM155. Further analyses revealed that, in accordance with their combined anti-survivin effects, YM155 significantly improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in xenograft models in vivo. Similar to pharmacologic inhibition of survivin, shRNA-mediated silencing of survivin expression not only inhibited RCC tumor growth, but also significantly sensitized RCC cells to temsirolimus therapy. Subsequent experiments demonstrated that the effectiveness of this dual survivin/mTOR inhibition strategy was mediated by a potent decrease in survivin levels and corresponding induction of apoptosis. Our findings establish survivin inhibition as a novel approach to improve RCC therapy that warrants further investigation.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Renal Cell; Cell Proliferation; Cell Survival; Disease Progression; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Imidazoles; Immunoblotting; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Kidney Neoplasms; Mice, Inbred BALB C; Mice, Nude; Naphthoquinones; Proliferating Cell Nuclear Antigen; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sirolimus; Survivin; Xenograft Model Antitumor Assays

Mesenchymal/metaplastic breast cancers (MpBCs) are often triple-negative (TNBC), and chemo-refractory, and can harbor phosphoinositide 3-kinase (PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity.. Patients with mesenchymal/MpBC treated with temsirolimus-based regimens were evaluated. Mutational analyses [polymerase chain reaction (PCR)-based DNA sequencing method, mass spectrometric detection (Sequenom MassARRAY), or next-generation sequencing] as well as loss of phosphatase and tensin homolog (PTEN) (immunohistochemistry) were performed (archived tissue when available).. Twenty-three patients (one of whom was on two separate trials) were treated using temsirolimus-containing regimens: temsirolimus alone (n = 1 patient) or combined with the following: liposomal doxorubicin and bevacizumab (DAT, n = 18); liposomal doxorubicin (DT, n = 1); paclitaxel and bevacizumab (TAT, n = 2); paclitaxel (TT, n = 1); carboplatin and bevacizumab (CAT, n = 1). Response rate [complete response (CR) + partial response (PR)] was 25% across all regimens; 32% in the anthracycline-based regimens [DAT and DT (CR = 2, PR = 4; N = 19)]. An additional two patients achieved stable disease (SD) ≥6 months [total SD ≥6 months/CR/PR = 8 (33%)]. Molecular aberrations in the PI3K pathway were common: PIK3CA mutation = 6/15 (40%), PTEN mutation = 3/11 (27%), and PTEN loss = 2/11 (18%). A point mutation in the NF2 gene (K159fs*16; NF2 alterations can activate mTor) was found in one patient who attained CR (3+ years). Of the eight patients who achieved SD ≥6 months/CR/PR, all 4 patients with available tissue had a molecular aberration that activate the PIK3CA/Akt/mTOR axis: PIK3CA mutation = 2; PTEN loss = 1; NF2 aberration = 1.. DAT has activity in MpBCs including complete CRs. Molecular aberrations that can activate the PI3 K/Akt/mTOR axis are common in MpBC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Carboplatin; Class I Phosphatidylinositol 3-Kinases; Doxorubicin; Female; Follow-Up Studies; Humans; Mesoderm; Metaplasia; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Paclitaxel; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Polyethylene Glycols; Polymerase Chain Reaction; Prognosis; PTEN Phosphohydrolase; Sirolimus; Survival Rate; Young Adult

The mammalian target of rapamycin (mTOR) correlates with cell survival under hypoxia and regulates hypoxia-inducible factor-1α (HIF-1α), a key protein in hypoxia-related events. However, the role of mTOR in radio-resistance has not been fully investigated. Therefore, the effect of mTOR on the radio-resistance of cancer cells under hypoxia was evaluated using the mTOR inhibitor temsirolimus. Clonogenic survival was examined in the A549 human lung adenocarcinoma cell line under normoxia or hypoxia, with or without temsirolimus. An oxygen enhancement ratio (OER) was calculated using the D(10) values, the doses giving 10% survival. Western blotting was performed to investigate the effect of temsirolimus on mTOR and the HIF-1α pathway under normoxia and hypoxia. A549 cells showed a radio-resistance of 5.1 and 14.2 Gy, as indicated by D(10) values under normoxia and hypoxia, respectively; the OER was 2.8. The cell survival rates under hypoxia and with temsirolimus remarkably decreased compared with those under normoxia. The D(10) values of the cells under normoxia and hypoxia were 4.8 and 5.4 Gy, respectively (OER = 1.1). mTOR expression was suppressed by temsirolimus under both normoxia and hypoxia. HIF-1α expression decreased under hypoxia in the presence of temsirolimus. These results suggest that temsirolimus can overcome the radio-resistance induced by hypoxia. When the fact that mTOR acts upstream of HIF-1α is considered, our data suggest that the restoration of radiation sensitivity by temsirolimus under hypoxia may be associated with the suppression of the HIF-1α pathway. Temsirolimus could therefore be used as a hypoxic cell radio-sensitizer.

Topics: Cell Hypoxia; Cell Line, Tumor; Dose-Response Relationship, Radiation; Humans; Lung Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Radiotherapy Dosage; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

The mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role in numerous cellular processes involving growth, proliferation and survival. The purpose of this study was to investigate the anti-tumoral effect of the mTOR inhibitor (mTORi) CCI-779 in HNSCC cell lines and its potency in cisplatin- and cetuximab-resistant cells.. A panel of 10 HNSCC cell lines with differences in TP53 mutational status and basal cisplatin sensitivity and two isogenic models of acquired resistance to cisplatin and cetuximab, respectively were studied. Cell survival after treatment with CCI-779, cisplatin and cetuximab alone or in combination was determined by MTT assays. Potential predictive biomarkers for tumor cell sensitivity to CCI-779 were evaluated.. We observed considerable heterogeneity in sensitivity of HNSCC cell lines to CCI-779 monotherapy. Sensitivity was observed in TP53 mutated as well as wild-type cell lines. Total and p-EGFR expression levels but not the basal activity of the mTOR and MAPK signaling pathways were correlated with sensitivity to CCI-779. Resistant cells with increased EGFR activation could be sensitized by the combination of CCI-779 with cetuximab. Interestingly, cell lines with acquired resistance to cisplatin displayed a higher sensitivity to CCI-779 whereas cetuximab-resistant cells were less sensitive to the drug, but could be sensitized to CCI-779 by EGFR blockade.. Activity of CCI-779 in HNSCC cells harboring TP53 mutations and displaying a phenotype of cisplatin resistance suggests its clinical potential even in patients with dismal outcome after current standard treatment. Cetuximab/mTORi combinations might be useful for treatment of tumors with high expression of EGFR/p-EGFR and/or acquired cetuximab resistance. This combinatorial treatment modality needs further evaluation in future translational and clinical studies.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cetuximab; Cisplatin; Drug Resistance, Neoplasm; ErbB Receptors; Head and Neck Neoplasms; Humans; Mutation; RNA, Messenger; Signal Transduction; Sirolimus; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases

Activated mammalian target of rapamycin (P-mTOR) has been shown to maintain the sensitivity of subsets of small-diameter primary afferent A-nociceptors. Local or systemic inhibition of the mTOR complex 1 (mTORC1) pathway reduced punctate mechanical and cold sensitivity in neuropathic pain and therefore offered a new approach to chronic pain control. In this study, we have investigated the effects of the rapamycin analog temsirolimus (CCI-779) on itch. Bouts of scratching induced by the histamine-dependent pruritogenic compound 48/80 and histamine-independent pruritogens, chloroquine and SLIGRL-NH2, injected intradermally were significantly reduced by local (intradermal) or systemic (intraperitoneal, i.p.) pretreatment with CCI-779. We also investigated the action of metformin, a drug taken to control type 2 diabetes and recently shown to inhibit mTORC1 in vivo. Although the response to nonhistaminergic stimuli was reduced at all of the time points tested, scratching to compound 48/80 was modified by metformin only when the drug was injected 24 hours before this pruritogen. We also examined the colocalization of P-mTOR with gastrin-releasing peptide, a putative marker for some itch-sensitive primary afferents, and found that P-mTOR was coexpressed in less than 5% of gastrin-releasing peptide-positive fibers in the mouse skin. Taken together, the data highlight the role that P-mTOR-positive A-fibers play in itch signaling and underline the importance of the mTORC1 pathway in the regulation of homeostatic primary afferent functions such as pain and itch. The actions of the antidiabetic drug metformin in ameliorating nonhistamine-mediated itch also suggest a new therapeutic route for the control of this category of pruritus.

Topics: Animals; Disease Models, Animal; Gastrin-Releasing Peptide; Histamine; Hypoglycemic Agents; Male; Mechanistic Target of Rapamycin Complex 1; Metformin; Mice; Mice, Inbred C57BL; Multiprotein Complexes; Neuralgia; Phosphoproteins; Protein Kinase Inhibitors; Pruritus; Signal Transduction; Sirolimus; Skin; TOR Serine-Threonine Kinases; Treatment Outcome

The insulin-like growth factors (IGFs), IGF-1 and IGF-2, have been implicated in the growth, survival and metastasis of a broad range of malignancies including pediatric tumors. They bind to the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR) which are overexpressed in many types of solid malignancies. Activation of the IR by IGF-2 results in increased survival of tumor cells. We have previously identified a novel human monoclonal antibody, m708.5, which binds with high (pM) affinity to both human IGF-1 and IGF-2, and potently inhibits phosphorylation of the IGF-1R and the IR in tumor cells. m708.5 exhibited strong antitumor activity as a single agent against most cell lines derived from neuroblastoma, Ewing family of tumor, rhabdomyosarcoma and osteosarcoma. When tested in neuroblastoma cell lines, it showed strong synergy with temsirolimus and synergy with chemotherapeutic agents in vitro. In xenograft models, the combination of m708.5 and temsirolimus significantly inhibited neuroblastoma growth and prolonged mouse survival. Taken together, these results support the clinical development of m708.5 for pediatric solid tumors with potential for synergy with chemotherapy and mTOR inhibitors.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Drug Synergism; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Mice, SCID; Neuroblastoma; Protein Binding; Sirolimus; Xenograft Model Antitumor Assays

To assess the impact of baseline chronic kidney disease on targeted therapy (TT)-induced toxicities and survival in patients treated for metastatic renal cell carcinoma (mRCC). Data from patients receiving first-line TT from January 2006 to June 2012 were collected retrospectively. TT side effects, time to treatment failure (TTF), and overall survival (OS) were analyzed according to the baseline glomerular filtration rate (GFR) calculated using the modification diet in renal disease formula. Hundred and two patients treated with sunitinib (N=67), sorafenib (N=24), or temsirolimus (N=11) were included. Forty-two patients (41%) had baseline chronic kidney disease with GFR less than 60 ml/min/1.73 m. Patients with GFR less than 60 were more likely to encounter severe (grade 3-4) TT-induced toxicities (79 vs. 32%, P<0.0001). Moreover, renal function impairment was significantly associated with higher median TTF and OS (respectively, 12 vs. 6 months for TTF, P=0.003; and 33 vs. 13 months for OS, P=0.001). On multivariate analysis, GFR less than 60 was identified as the only factor associated with a higher rate of severe toxicity: odds ratio=4.74 (1.67-13.41), P=0.003. Severe toxicity (P=0.05) was identified as an independent prognostic factor for OS and TTF. Baseline chronic kidney disease was associated with higher TT-induced toxicities, which were identified as a prognostic factor of higher survival in mRCC treatment. These results suggest that GFR measurement could be used to optimize the efficacy of TT in patients treated for an mRCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Chronic Disease; Female; Glomerular Filtration Rate; Humans; Indoles; Kidney Diseases; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate

The relation between hematocrit, substance concentration, extraction recovery and spot formation of tacrolimus, sirolimus, everolimus, ascomycin, temsirolimus and cyclosporin A was investigated for Whatman 31 ET CHR, Whatman FTA DMPK-C, Whatman 903, Perkin Elmer 226 and Agilent Bond Elut DMS DBS cards.. We found that all DBS cards showed the same hematocrit and concentration-dependent recovery patterns for sirolimus, everolimus and temsirolimus. At high concentrations, the total hematocrit effects were much more pronounced than at low concentrations for tacrolimus, sirolimus, everolimus, ascomycin and temsirolimus.. The tested card types showed differences in performance, especially at extreme concentrations and hematocrit values. It may be useful to investigate the performance of different types of DBS cards prior to analytical method validation.

Topics: Cyclosporine; Dried Blood Spot Testing; Everolimus; Hematocrit; Humans; Immunosuppressive Agents; Sirolimus; Tacrolimus

Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2-positive breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+ breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib (SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells (SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic interactions in lapatinib- and dual- resistant cells and improved the results of pertuzumab plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients showed strong response to the antitumor activity of the combination of EGCG with pertuzumab or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Catechin; Cell Adhesion; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fatty Acid Synthase, Type I; Female; Gallic Acid; Humans; Lapatinib; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Naphthalenes; Neoplasm Invasiveness; Neoplasm Transplantation; Quinazolines; Receptor, ErbB-2; Signal Transduction; Sirolimus; Trastuzumab

Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB=30-66%, ABC=45-57%). Combination treatment with the PI3K-δ inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB=16-38%, ABC=25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus+bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction.

Topics: Adenine; Antineoplastic Agents; Bortezomib; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Antagonism; Drug Synergism; Humans; Lymphoma, Large B-Cell, Diffuse; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; Sirolimus

The mechanistic target of rapamycin (mTOR) promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. We hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in vivo by limiting tumour cell growth, abrogating tumour angiogenesis and modulating immune/inflammatory tumour milieu.. We produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space of C57BL/6 and BALB/c mice, respectively. Animals were given five times/week intraperitoneal injections of 20 mg/kg temsirolimus or vehicle and were sacrificed on day 26 (flank) or on day 15 (pleural) post-tumour cell propagation.. Temsirolimus limited mesothelioma growth in vivo by stimulating tumour cell apoptosis, inhibiting tumour angiogenesis, enhancing tumour lymphocyte abundance and blocking pro-tumour myeloid cell recruitment. Pleural fluid accumulation was significantly mitigated in AE17 but not in AB1 mesotheliomas. In vitro, temsirolimus hindered mesothelioma cell growth, NF-kappaB activation and macrophage migration.. In conclusion, temsirolimus apart from inducing tumour cell apoptosis, targets tumour angiogenesis and influences inflammatory tumour microenvironment to halt experimental mesothelioma growth in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neovascularization, Pathologic; NF-kappa B; Pleural Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Microenvironment

The MTT assay (to a less degree MTS, XTT or WST) is a widely exploited approach for measuring cell viability/drug cytotoxicity. MTT reduction occurs throughout a cell and can be significantly affected by a number of factors, including metabolic and energy perturbations, changes in the activity of oxidoreductases, endo-/exocytosis and intracellular trafficking. Over/underestimation of cell viability by the MTT assay may be due to both adaptive metabolic and mitochondrial reprogramming of cells subjected to drug treatment-mediated stress and inhibitor off-target effects. Previously, imatinib, rottlerin, ursolic acid, verapamil, resveratrol, genistein nanoparticles and some polypeptides were shown to interfere with MTT reduction rate resulting in inconsistent results between the MTT assay and alternative assays. Here, to test the under/overestimation of viability by the MTT assay, we compared results derived from the MTT assay with the trypan blue exclusion assay after treatment of glioblastoma U251, T98G and C6 cells with three widely used inhibitors with the known direct and side effects on energy and metabolic homeostasis - temozolomide (TMZ), a DNA-methylating agent, temsirolimus (TEM), an inhibitor of mTOR kinase, and U0126, an inhibitor of MEK1/2 kinases. Inhibitors were applied shortly as in IC50 evaluating studies or long as in studies focusing on drug resistance acquisition. We showed that over/underestimation of cell viability by the MTT assay and its significance depends on a cell line, a time point of viability measurement and other experimental parameters. Furthermore, we provided a comprehensive survey of factors that should be accounted in the MTT assay. To avoid result misinterpretation, supplementation of the tetrazolium salt-based assays with other non-metabolic assays is recommended.

Topics: Animals; Biological Assay; Cell Count; Cell Line, Tumor; Cell Survival; Dacarbazine; Female; Formazans; Humans; Inhibitory Concentration 50; Rats; Rats, Wistar; Sirolimus; Temozolomide; Tetrazolium Salts

Effective choice of anticancer drugs is important problem of modern medicine. We developed a method termed OncoFinder for the analysis of new type of biomarkers reflecting activation of intracellular signaling and metabolic molecular pathways. These biomarkers may be linked with the sensitivity to anticancer drugs. In this study, we compared the experimental data obtained in our laboratory and in the Genomics of Drug Sensitivity in Cancer (GDS) project for testing response to anticancer drugs and transcriptomes of various human cell lines. The microarray-based profiling of transcriptomes was performed for the cell lines before the addition of drugs to the medium, and experimental growth inhibition curves were built for each drug, featuring characteristic IC50 values. We assayed here four target drugs - Pazopanib, Sorafenib, Sunitinib and Temsirolimus, and 238 different cell lines, of which 11 were profiled in our laboratory and 227 - in GDS project. Using the OncoFinder-processed transcriptomic data on ~600 molecular pathways, we identified pathways showing significant correlation between pathway activation strength (PAS) and IC50 values for these drugs. Correlations reflect relationships between response to drug and pathway activation features. We intersected the results and found molecular pathways significantly correlated in both our assay and GDS project. For most of these pathways, we generated molecular models of their interaction with known molecular target(s) of the respective drugs. For the first time, our study uncovered mechanisms underlying cancer cell response to drugs at the high-throughput molecular interactomic level.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomics; HeLa Cells; Hep G2 Cells; Humans; Indazoles; Indoles; Inhibitory Concentration 50; Jurkat Cells; MCF-7 Cells; Neoplasms; Niacinamide; Oligonucleotide Array Sequence Analysis; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Transcriptome

Although narrow eligibility criteria improve the internal validity of clinical trials, they may result in differences between study populations and real-world patients, threatening generalizability. Therefore, we evaluated whether patients treated for metastatic renal cell cancer (mRCC) in routine clinical practice are similar to those enrolled onto clinical trials.. In this cohort study, we compared baseline characteristics of patients with mRCC in phase III clinical trials of new targeted therapies and those in a retrospective registry composed of academic (Duke) and community (ACORN Network) practices.. A total of 438 registry patients received sunitinib, sorafenib, temsirolimus, or pazopanib (most commonly used agents) in first-line treatment. Registry patients receiving tyrosine kinase inhibitors (sunitinib, sorafenib, or pazopanib) were more likely to have poor-risk disease by Memorial Sloan Kettering Cancer Center criteria (poor, 7.4% v 2.9%; P < .001; favorable, 30.1% v 43.8%; P < .001) and to have impaired performance status (Eastern Cooperative Oncology Group > 1, 11.1% v 0.6%; P < .001). However, registry patients receiving temsirolimus were less likely to have poor-risk disease (poor, 10.2% v 69.4%; P < .001; favorable, 16.9% v 0%; P < .001). Thus, 39.0% of registry patients would have been excluded from the phase III clinical trial testing the drug they received.. Patients with mRCC treated with tyrosine kinase inhibitors in real-world clinical practice are sicker than those enrolled onto pivotal clinical trials, and more than one third are trial ineligible. Application of clinical trial findings to dissimilar populations may result in patient harm. Clinical research with more inclusive eligibility criteria is needed to appropriately guide real-world practice.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Patients; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Renal cell carcinoma is one of the most chemoresistant cancers, and its metastatic form requires administration of targeted therapies based on angiogenesis or mTOR inhibitors. Understanding how these treatments impact the human metabolism is essential to predict the host response and adjust personalised therapies. We present a metabolomic investigation of serum samples from patients with metastatic RCC (mRCC) to identify metabolic signatures associated with targeted therapies.. Pre-treatment and serial on-treatment sera were available for 121 patients participating in the French clinical trial TORAVA, in which 171 randomised patients with mRCC received a bevacizumab and temsirolimus combination (experimental arm A) or a standard treatment: either sunitinib (B) or interferon-α+bevacizumab (C). Metabolic profiles were obtained using nuclear magnetic resonance spectroscopy and compared on-treatment or between treatments.. Multivariate statistical modelling discriminates serum profiles before and after several weeks of treatment for arms A and C. The combination A causes faster changes in patient metabolism than treatment C, detectable after only 2 weeks of treatment. Metabolites related to the discrimination include lipids and carbohydrates, consistently with the known RCC metabolism and side effects of the drugs involved. Comparison of the metabolic profiles for the three arms shows that temsirolimus, an mTOR inhibitor, is responsible for the faster host metabolism modification observed in the experimental arm.. In mRCC, metabolomics shows a faster host metabolism modification induced by a mTOR inhibitor as compared with standard treatments. These results should be confirmed in larger cohorts and other cancer types.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Female; Humans; Indoles; Interferon-alpha; Kidney Neoplasms; Male; Metabolome; Middle Aged; Pyrroles; Serum; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL.

Topics: Adult; Antineoplastic Agents; Apoptosis; Biomimetics; Biphenyl Compounds; Blotting, Western; Cell Cycle; Cell Proliferation; Child; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Peptide Fragments; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end-diastolic pressure (LVEDP)-dependent manner, mTOR inhibition suppressed eccentric hypertrophy and induced cardiac atrophy even under VO. Notably, Akt was ubiquitinated and phosphorylated in response to VO, and blocking the recruitment of Akt to the membrane completely abolished mTOR activation. Various growth factors were upregulated during VO, suggesting that these might be involved in Akt-mTOR activation. Furthermore, the rate of eccentric hypertrophy progression was proportional to mTOR activity, which allowed accurate estimation of eccentric hypertrophy by time-integration of mTOR activity. These results suggested that the Akt-mTOR axis plays a pivotal role in eccentric hypertrophy, and mTOR activity quantitatively determines the rate of eccentric hypertrophy progression. As eccentric hypertrophy is an inherent system of the heart for regulating cardiac output and LVEDP, our findings provide a new mechanistic insight into the adaptive mechanism of the heart.

Topics: Animals; Arteriovenous Fistula; Echocardiography; Heart; Hemodynamics; Hypertrophy, Left Ventricular; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitination; Up-Regulation

Topics: Administration, Intravenous; Adult; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Compassionate Use Trials; Endometrial Neoplasms; Female; Follow-Up Studies; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Retrospective Studies; Sirolimus; Survival Analysis; Treatment Outcome

The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy of metastatic renal cell carcinoma (mRCC).. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Six international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Association for Urology (2013), the European Society of Medical Oncology (2012), the National Institute of Health and Clinical Excellence (2011), the Canadian Kidney Cancer Forum (2013) and the Asian Oncology Summit (2012). Recommendations on the first-, second- and third-line treatment for mRCC were developed.. These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of mRCC.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Singapore; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

The SCAN gynaecological cancers systemic therapy workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the systemic therapy of endometrial (uterine) cancer.. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Three international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2015), the European Society of Medical Oncology (2013) and the Cancer Council Australia (2011). Recommendations on the role of chemotherapy following surgery in women diagnosed with endometrial cancer, the chemotherapeutic options for women with advanced or recurrent endometrial cancers and the role of chemotherapy in women with uterine papillary serous carcinoma or clear cell carcinoma were developed.. These adapted guidelines form the SCAN Guidelines 2015 for the systemic therapy of endometrial (uterine) cancer.

Topics: Adenocarcinoma, Clear Cell; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Carboplatin; Carcinoma, Endometrioid; Chemotherapy, Adjuvant; Cisplatin; Endometrial Neoplasms; Female; Humans; Hysterectomy; Neoplasm Recurrence, Local; Neoplasms, Cystic, Mucinous, and Serous; Paclitaxel; Progestins; Singapore; Sirolimus; Tamoxifen

B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G0/G1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.

Topics: Apoptosis; Autophagy; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Everolimus; Heterocyclic Compounds, 3-Ring; Humans; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Oxadiazoles; Phosphoinositide-3 Kinase Inhibitors; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To evaluate experience of the use of temsirolimus for metastatic renal cell carcinoma (mRCC) in a single center in Japan.. This study included 55 consecutive patients with mRCC who received temsirolimus in a routine clinical setting, and retrospectively reviewed the comprehensive outcomes of these patients.. Of the 55 patients, 20 had a Karnofsky performance status of ≤80, and 5, 41 and 9 were classified into favorable, intermediate and poor risk groups, respectively, according to the Memorial Sloan-Kettering Cancer Center model. Initially, 25 mg of temsirolimus was applied weekly; however, dose modification was required in 19 patients, resulting in a relative dose intensity of 90.5 % throughout this series. As the best responses to temsirolimus, 4, 44 and 7 were judged to have a partial response, stable disease and progressive disease, respectively. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of temsirolimus was 7.0 and 25.0 months, respectively. Of several factors examined, only the pretreatment C-reactive protein level was shown to be independently associated with both PFS and OS. The common adverse events related to temsirolimus corresponding to ≥grade 3 were anemia in 4, thrombocytopenia in 3, stomatitis in 3 and hyperglycemia in 3. Quality of life analysis using 36-Item Short Form showed that there were no significant differences in any scale scores between surveys performed before and 3 months after the introduction of temsirolimus.. Temsirolimus was well tolerated and facilitated comparatively favorable cancer control in Japanese patients with mRCC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; C-Reactive Protein; Carcinoma, Renal Cell; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Japan; Karnofsky Performance Status; Male; Middle Aged; Quality of Life; Sirolimus; Treatment Outcome

To analyze the cytotoxic action of temsirolimus using 3 established human bladder cancer cell lines and to assess whether temsirolimus potentiates the anticancer activity of gemcitabine and cisplatin.. Temsirolimus (500, 1,000, 2,000, and 4,000 nM), in isolation, and combined with gemcitabine (100 nM) and cisplatin (2.5 µg/ml), was given to 5637, T24, and HT1376 bladder cancer cell lines. Cell proliferation, autophagy, early apoptosis, and cell cycle distribution were analyzed after a 72-hour period. The expression of mammalian target of rapamycin baseline, Akt, and their phosphorylated forms, before and after treatment with temsirolimus, was evaluated by immunoblotting.. Temsirolimus slightly decreased the bladder cancer cell proliferation in all 3 cell lines. No significant differences in the expression of mammalian target of rapamycin, Akt, and their phosphorylated forms because of temsirolimus exposure were found in the 3 cell lines. As part of a combined regime along with gemcitabine, and especially with cisplatin, there was a more pronounced antiproliferative effect. This pattern of response was similar to the other parameters analyzed (increased autophagy and apoptosis). Also, in the combined regime, an enhanced cell cycle arrest in the G0/G1 phase was observed. The non-muscle invasive 5637 bladder cancer cell line was most sensitive to both combinations.. Temsirolimus makes a moderate contribution in terms of cell proliferation, apoptosis, and autophagy. However, it does potentiate the activity of gemcitabine and particularly cisplatin. Therefore, cisplatin- or gemcitabine-based chemotherapy regimen used in combination with temsirolimus to treat bladder cancer represents a novel and valuable treatment option, which should be tested for future studies in urinary bladder xenograft models.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Gemcitabine; Humans; Immunoblotting; Microscopy, Fluorescence; Phosphorylation; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Urinary Bladder Neoplasms

To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC).. Retrospective review of 310 patients with mRCC who received temsirolimus and/or everolimus between June 2007 and October 2010. Clinical correlations were made with serial radiological imaging. Fisher's exact, Wilcoxon rank-sum, and logistic regression analyses were used to evaluate the association of NIP with demographic or clinical factors. Log-rank and Cox proportional hazards regression analyses were used for the time-to-event analysis.. NIP occurred in 6% of temsirolimus-treated and 23% of everolimus-treated patients. Symptoms included cough, dyspnoea, and fever (median of two and three symptoms per patient, respectively). The median National Cancer Institute Common Toxicity Criteria for Adverse Events pneumonitis grade was 2 for both groups. Older age and everolimus treatment were predictive of NIP. Patients who developed NIP had a significantly longer time on treatment (median 4.1 vs 2 months) and overall survival (OS) (median 15.4 vs 7.4 months). NIP was a predictor of improved OS by multivariate analysis.. There was an increased incidence of NIP in everolimus-treated patients. Improved OS in patients who developed NIP is an intriguing finding and should be further investigated. Given the incidence, morbidity, and outcomes seen in patients on everolimus who develop NIP, management should include proactive monitoring and treatment of NIP with the goal of preserving mTOR inhibitor therapy.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bronchodilator Agents; Carcinoma, Renal Cell; Everolimus; Female; Hospitalization; Humans; Kidney Neoplasms; Male; Middle Aged; Oxygen; Pneumonia; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

A 55-year-old Japanese man was admitted to Oita University Hospital (Oita, Japan) for pyrexia, malaise and dyspnea, and abnormal shadows on chest radiographs. He had started receiving sunitinib (37.5 mg a day for 3 weeks, followed by a 3-week break before beginning the next dosing cycle) for metastatic renal cell carcinoma after the improvement of temsirolimus-induced interstitial pneumonia. Sunitinib is a multiple tyrosine kinase receptor inhibitor approved for the treatment of metastatic renal cell carcinoma, and the most common clinical adverse effects of sunitinib are diarrhea, mucositis, stomatitis, hypertension, rashes and altered taste. We herein report a rare case of sunitinib-related interstitial pneumonia after treatment with temsirolimus for metastatic renal cell carcinoma. This case suggests the possibility of recall phenomenon of drug-induced pneumonia during the administration of additional chemotherapy.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Pyrroles; Radiography; Sirolimus; Sunitinib

mTOR is a rational target in renal cell carcinoma (RCC) because of its role in disease progression. However, the effects of temsirolimus, the only first-generation mTOR inhibitor approved by the FDA for first-line treatment of metastatic RCC, on tumor reduction and progression-free survival are minimal. Second-generation mTOR inhibitors have not been evaluated on RCC. We compared the effects of temsirolimus and MLN0128, a potent second-generation mTOR inhibitor, on RCC growth and metastasis using a realistic patient-derived tissue slice graft (TSG) model. TSGs were derived from three fresh primary RCC specimens by subrenal implantation of precision-cut tissue slices into immunodeficient mice that were randomized and treated with MLN0128, temsirolimus, or placebo. MLN0128 consistently suppressed primary RCC growth, monitored by magnetic resonance imaging (MRI), in three TSG cohorts for up to 2 months. Temsirolimus, in contrast, only transiently inhibited the growth of TSGs in one of two cohorts before resistance developed. In addition, MLN0128 reduced liver metastases, determined by human-specific quantitative polymerase chain reaction, in two TSG cohorts, whereas temsirolimus failed to have any significant impact. Moreover, MLN0128 decreased levels of key components of the two mTOR subpathways including TORC1 targets 4EBP1, p-S6K1, HIF1α and MTA1 and the TORC2 target c-Myc, consistent with dual inhibition. Our results demonstrated that MLN0128 is superior to temsirolimus in inhibiting primary RCC growth as well as metastases, lending strong support for further clinical development of dual mTOR inhibitors for RCC treatment.

Topics: Adult; Animals; Benzoxazoles; Carcinoma, Renal Cell; Drug Screening Assays, Antitumor; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Kidney Neoplasms; Liver Neoplasms; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Knockout; Middle Aged; Multiprotein Complexes; Protein Kinase Inhibitors; Pyrimidines; Random Allocation; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The objective of this study was to analyze the expression levels of multiple components in the mammalian target of rapamycin (mTOR) signaling pathway in radical nephrectomy specimens from patients with metastatic renal-cell carcinoma (RCC) treated with mTOR inhibitors in order to identify factors predicting susceptibility to these agents. This study retrospectively included a total of 48 consecutive patients undergoing radical nephrectomy, who were diagnosed with metastatic RCC and subsequently treated with an mTOR inhibitor (everolimus or temsirolimus) as either first- or second-line systemic therapy. Expression levels of 5 molecular markers involved in the signaling pathway associated with mTOR, including PTEN, phosphorylated (p)-Akt, p-mTOR, p-p70 ribosomal S6 kinase, and p-4E-binding protein 1 (4E-BP1), were measured by immunohistochemical staining of primary RCC specimens. Of several factors examined, bone metastasis, liver metastasis, and the expression level of p-4E-BP1 were shown to have significant impacts on the response to the mTOR inhibitors. Progression-free survival (PFS) was significantly correlated with the expression levels of PTEN and p-4E-BP1 in addition to the presence of bone metastasis on univariate analysis. Of these significant factors, p-4E-BP1 expression and bone metastasis appeared to be independently associated with PFS on multivariate analysis. These findings suggest that it would be useful to consider the expression levels of potential molecular markers in the mTOR signaling pathway, particularly p-4E-BP1, as well as conventional clinical parameters when selecting patients with metastatic RCC who are likely to benefit from treatment with mTOR inhibitors.

Topics: Adaptor Proteins, Signal Transducing; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Cycle Proteins; Disease-Free Survival; Everolimus; Female; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Nephrectomy; Phosphoproteins; Phosphorylation; Prognosis; Retrospective Studies; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Renal cell carcinomas (RCCs) represent one of the ten leading cancer entities with an increasing incidence especially in the western world. Unfortunately, about 25% of the patients develop metastatic RCC (mRCC) associated with a most unfavorable prognosis. In the recent years, various new agents targeting VEGF or VEGF receptor (VEGFR) or the mTOR pathway have been approved for the treatment of mRCC with significant prolongation of progression-free survival and, in part, of overall survival (OS). Targeting the mTOR kinase is an interesting option for mRCC. Temsirolimus, one of the available mTOR inhibitors, has been approved as a single agent in poor-risk mRCC patients based on the pivotal Phase III trial showing a significant superiority in OS versus IFN-α or temsirolimus + IFN-α, which has been verified by a pivotal Phase III trial. The benefit has been shown for clear cell carcinoma and papillary RCC as well. For poor prognosis patients, temsirolimus improves median survival by 3.6 months. In second-line treatment compared with sorafenib following first-line treatment with sunitinib temsirolimus showed a relative progression-free survival benefit for patients with nonclear cell RCC with temsirolimus. The median OS for the temsirolimus group was 12.27 and 16.64 months for the sorafenib group. In 2007, the US FDA granted approval for temsirolimus for the treatment of advanced RCC.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Prognosis; Protein Kinase Inhibitors; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases

To compare outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus, temsirolimus, and sorafenib following initial treatment with a tyrosine kinase inhibitor (TKI) in community and academic practices throughout the US.. Medical records of mRCC patients who received everolimus, temsirolimus or sorafenib as their second therapy following a TKI were retrospectively reviewed from a nationally representative panel of oncologists. Overall survival (OS) and progression-free survival (PFS) of second targeted therapies were compared using multivariable Cox proportional hazard models, with adjustment for demographics, disease severity and prior treatments.. A total of 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib, respectively, as second targeted therapies were included. Eighty-six percent used sunitinib and the remainder used sorafenib or pazopanib as their initial TKI. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS (hazard ratio [HR] 0.60; CI 0.42-0.85; p = 0.004) and PFS (HR 0.73; CI 0.54-0.97; p = 0.032) compared to temsirolimus. Everolimus was associated with significantly longer OS (HR 0.66; CI 0.44-0.99; p = 0.045) and numerically longer PFS compared to sorafenib. No significant differences were observed between temsirolimus and sorafenib.. Despite adjustment for multiple patient characteristics, comparisons between treatment groups may be confounded by unobserved factors in this retrospective observational study. Tolerability outcomes were not collected.. In this retrospective, non-randomized study of mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; Sorafenib; Treatment Outcome

We report the identification of an FBXW7 mutation in a patient with adenocarcinoma of the lung, whose tumor had previously been shown to be EGFR and ALK wild type and who had previously progressed on multiple lines of systemic therapy. She experienced both clinical and radiographic benefit from treatment with the mTOR inhibitor temsirolimus.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cell Cycle Proteins; Drug Resistance, Neoplasm; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Female; Glutamates; Guanine; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Middle Aged; Molecular Targeted Therapy; Motor Activity; Mutation; Neoplasm Metastasis; Pemetrexed; Recurrence; Remission Induction; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases; Weight Gain

The mTOR inhibitor temsirolimus has antitumor and antiangiogenic activity against several carcinomas, yet few reports document the efficacy of temsirolimus against malignant pleural mesothelioma (MPM). Therefore, we evaluated the efficacy of temsirolimus and the antiangiogenic effect of temsirolimus in the treatment of MPM. We examined the efficacy of temsirolimus alone and the efficacy of the combination of temsirolimus and cisplatin or pemetrexed against four MPM cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The effect of temsirolimus on the production of proangiogenic cytokines by MPM cell lines was examined by enzyme-linked immunosorbent assay (ELISA). Expression of mTOR and proangiogenic cytokines in clinical specimens from MPM patients was determined by immunohistochemistry. Temsirolimus inhibited cell viability and suppressed cell proliferation of all MPM cell lines. Combined treatment with temsirolimus and cisplatin inhibited the viability of all MPM cell lines more effectively than temsirolimus alone. Temsirolimus strongly inhibited the phosphorylation of p70s6k, a downstream molecule of mTOR, in all MPM cell lines and led to an increase in the levels of cleaved caspase-3 in the H226 and Y-meso14 cells. Temsirolimus also inhibited the production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-AA (PDGF-AA). Phosphorylated mTOR and high expression of VEGF and PDGF were detected in 2 and 3, respectively, out of the 5 MPM specimens. These results suggest that temsirolimus has activity against MPM cells by inhibition of cell proliferation and angiogenesis, and may be beneficial for a subset of MPM patients with high mTOR expression.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Drug Screening Assays, Antitumor; Drug Synergism; Glutamates; Guanine; Humans; Mesothelioma; Pemetrexed; Platelet-Derived Growth Factor; Pleural Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Although Hodgkin's lymphoma (HL) was one of the first human cancers to be cured by chemotherapy, no new agents other than brentuximab vedotin (Adcetris®, CD 30 directed antibody drug conjugate) have received US Food and Drug Administration (FDA) approval for HL since 1977. Subsets of young adult patients with HL continue to relapse, even after stem cell transplantation, warranting new approaches. Against this background, we report a dramatic response in a young patient with advanced HL refractory to the standard treatment who responded to the combination of a pan-histone deacetylase inhibitor (vorinostat, suberoylanilide hydroxamic acid, SAHA) and mammalian target of rapamycin (mTOR) inhibitor therapy (sirolimus,rapamume). In-depth immunohistochemical and morphoproteomic analyses of this exceptional responder to targeted therapy have yielded potential insights into the biology of advanced HL. The PI3K/AKT/mTOR pathway is a commonly activated pathway in multiple tumor types including HL. The patient was treated using therapy based on mechanistic in vitro data demonstrating that combined histone deacetylase (HDAC) and mTOR inhibition act together on this pathway, resulting in inhibition of reciprocal feedback networks, leading to better anti-proliferative activity. The in vivo response signature from this patient's tissue sample sheds light on immune dysregulation in HL. We describe the response signature achieved from targeting immune dysregulation in addition to targeting the key oncogenic PI3K/AKT/mTOR pathway. We also expand on the role of rapamycin analogs in oncology. This study supports a role for an immune-type pathogenesis that is amenable to immune modulating targeted therapy in refractory HL.. We report an exceptional responder to molecularly targeted and immune modulator therapy in advanced Hodgkin's lymphoma. The morphoproteomic/morphometric findings in this "unusual responder" patient's relapsed HL that correlate best, as a response signature with the subsequent clinical remission following rapamycin (sirolimus) and vorinostat (SAHA) therapies, center on an immune dysregulation involving an imbalance between effector and functional T regulatory cells in addition to targeting the mTOR pathway. This underscores the need for an approach illustrated in our study--namely of focusing on pathogenetic mechanisms and combinatorial therapies that target both the pathogenesis and adaptive responses to contemplated therapies.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Hodgkin Disease; Humans; Hydroxamic Acids; Immunologic Factors; Molecular Targeted Therapy; Phosphoinositide-3 Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Vorinostat

The clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC.. Baseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS).. Eighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC.. A subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

A dozen clinical trials examining a combination of temsirolimus and cetuximab in treating metastatic colon cancer are currently underway. We investigated the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in the synergism between temsirolimus and cetuximab in colon cancer.. Five colon cancer cell lines were used for in vitro studies. Signal transduction pathways were assessed by immunoblotting. The synergism between studied drugs was analyzed with combination indexes. Gene silencing was performed using small interfering RNAs. The efficacies of temsirolimus and cetuximab were tested in nude mice with colon cancer xenografts. Transcriptional activity was assessed using a reporter assay. The inhibitors leupeptin, chloroquine, and MG132 were used to assess protein degradation. The association between CIP2A, clinicopathological parameters, and survival was examined by immunohistochemical staining using a tumor tissue microarray.. Temsirolimus decreased the resistance of cells to cetuximab by both inhibiting transcription of CIP2A and increasing degradation of CIP2A through the lysosomal-autophagy pathway. The mammalian target of rapamycin (mTOR) protein immunoprecipitated along with CIP2A. Temsirolimus decreased expression of phosphorylated extracellular regulated protein kinase (pErk) and phosphorylated v-akt murine thymoma viral oncogene (pAKT) and decreased the interaction of CIP2A and mTOR in cell lines without the K-ras codon 12 mutation. CIP2A was a prognostic marker only in colon cancer patients with weak expression of pErk or pAKT.. Temsirolimus decreases cellular resistance to cetuximab by regulating CIP2A expression in colon cancer cells. Potential biomarkers for CIP2A inhibitors include pErk and pAKT.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autoantigens; Biomarkers, Tumor; Blotting, Western; Cell Proliferation; Cetuximab; Colonic Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Sirolimus

Chemotherapy for collecting duct carcinoma (CDC) has demonstrated only limited efficacy in the advanced setting. The present study evaluated the activity of targeted therapies in metastatic CDC.. We evaluated a cohort of 384 consecutive patients with metastatic renal cell carcinoma (mRCC). The characteristics of patients with CDC were compared against those of the remaining cohort. All patients with CDC were treated with targeted therapies.. Thirteen patients with advanced CDC were referred to our Center (incidence: 3.4% of all mRCC). Median age was 57 and 62 years in the CDC and non-CDC groups, respectively. The overall disease control in the CDC population was 23%, and median overall survival was 4 (95% confidence interval(CI)=2.4-5.6) months. Three patients obtained a satisfying response (disease control lasting 6-33 months).. CDC has a poor prognosis compared to non-CDC renal cell carcinoma. Treatment for CDC represents a future challenge and targeted therapies may play a role in selected cases.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Indoles; Kidney Neoplasms; Male; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Pneumonia; Sirolimus

Statistical challenges arise from modern biomedical studies that produce time course genomic data with ultrahigh dimensions. In a renal cancer study that motivated this paper, the pharmacokinetic measures of a tumor suppressor (CCI-779) and expression levels of 12,625 genes were measured for each of 33 patients at 8 and 16 weeks after the start of treatments, with the goal of identifying predictive gene transcripts and the interactions with time in peripheral blood mononuclear cells for pharmacokinetics over the time course. The resulting data set defies analysis even with regularized regression. Although some remedies have been proposed for both linear and generalized linear models, there are virtually no solutions in the time course setting. As such, a novel GEE-based screening procedure is proposed, which only pertains to the specifications of the first two marginal moments and a working correlation structure. Different from existing methods that either fit separate marginal models or compute pairwise correlation measures, the new procedure merely involves making a single evaluation of estimating functions and thus is extremely computationally efficient. The new method is robust against the mis-specification of correlation structures and enjoys theoretical readiness, which is further verified via Monte Carlo simulations. The procedure is applied to analyze the aforementioned renal cancer study and identify gene transcripts and possible time-interactions that are relevant to CCI-779 metabolism in peripheral blood.

Topics: Antineoplastic Agents; Biometry; Clinical Trials, Phase II as Topic; Gene Expression Profiling; Humans; Kidney Neoplasms; Linear Models; Models, Statistical; Monte Carlo Method; Sirolimus; Time Factors

Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3(+) T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3(+) T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients.

Topics: Animals; Cancer Vaccines; Female; Forkhead Transcription Factors; Humans; Immunologic Memory; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Sirolimus; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases

Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.

Topics: Animals; Antigens, CD34; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzofurans; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Leukemia; Leukocytes, Mononuclear; Mice; Mitochondria; Neoplastic Stem Cells; Phenotype; Reactive Oxygen Species; Sirolimus; Stem Cells; Triterpenes; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Due to their high prevalence, retinal vascular diseases including age related macular degeneration (AMD), retinal vein occlusions (RVO), diabetic retinopathy (DR) and diabetic macular edema have been major therapeutic targets over the last years. The pathogenesis of these diseases is complex and yet not fully understood. However, increased proliferation, migration and angiogenesis are characteristic cellular features in almost every retinal vascular disease. The introduction of vascular endothelial growth factor (VEGF) binding intravitreal treatment strategies has led to great advances in the therapy of these diseases. While the predominant part of affected patients benefits from the specific binding of VEGF by administering an anti-VEGF antibody into the vitreous cavity, a small number of non-responders exist and alternative or additional therapeutic strategies should therefore be evaluated. The mammalian target of rapamycin (mTOR) is a central signaling pathway that eventually triggers up-regulation of cellular proliferation, migration and survival and has been identified to play a key role in angiogenesis. In the present study we were able to show that both retinal pigment epithelial (RPE) cells as wells as human umbilical vein endothelial cells (HUVEC) are inhibited in proliferating and migrating after treatment with temsirolimus in non-toxic concentrations. Previous studies suggest that the production of VEGF, platelet derived growth factor (PDGF) and other important cytokines is not only triggered by hypoxia but also by mTOR itself. Our results indicate that temsirolimus decreases VEGF and PDGF expression on RNA and protein levels significantly. We therefore believe that the mTOR inhibitor temsirolimus might be a promising drug in the future and it seems worthwhile to evaluate complementary therapeutic effects with anti-VEGF drugs for patients not profiting from mono anti-VEGF therapy alone.

Topics: Adult; Blotting, Western; Cell Movement; Cell Proliferation; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Middle Aged; Platelet-Derived Growth Factor; Real-Time Polymerase Chain Reaction; Retinal Pigment Epithelium; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases

Accumulation of amyloid-β peptides (Aβ) within brain is a major pathogenic hallmark of Alzheimer's disease (AD). Emerging evidence suggests that autophagy, an important intracellular catabolic process, is involved in Aβ clearance. Here, we investigated whether temsirolimus, a newly developed compound approved by Food and Drug Administration and European Medicines Agency for renal cell carcinoma treatment, would promote autophagic clearance of Aβ and thus provide protective effects in cellular and animal models of AD. HEK293 cells expressing the Swedish mutant of APP695 (HEK293-APP695) were treated with vehicle or 100nM temsirolimus for 24h in the presence or absence of 3-methyladenine (5mM) or Atg5-siRNA, and intracellular Aβ levels as well as autophagy biomarkers were measured. Meanwhile, APP/PS1 mice received intraperitoneal injection of temsirolimus (20mg/kg) every 2 days for 60 days, and brain Aβ burden, autophagy biomarkers, cellular apoptosis in hippocampus, and spatial cognitive functions were assessed. Our results showed that temsirolimus enhanced Aβ clearance in HEK293-APP695 cells and in brain of APP/PS1 mice in an autophagy-dependent manner. Meanwhile, temsirolimus attenuated cellular apoptosis in hippocampus of APP/PS1 mice, which was accompanied by an improvement in spatial learning and memory abilities. In conclusion, our study provides the first evidence that temsirolimus promotes autophagic Aβ clearance and exerts protective effects in cellular and animal models of AD, suggesting that temsirolimus administration may represent a new therapeutic strategy for AD treatment. Meanwhile, these findings emphasize the notion that many therapeutic agents possess pleiotropic actions aside from their main applications.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antineoplastic Agents; Autophagy; Brain; Disease Models, Animal; HEK293 Cells; Humans; Male; Maze Learning; Memory; Mice, Transgenic; Neuroprotective Agents; Sirolimus; TOR Serine-Threonine Kinases

Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity.. The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC.. We conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials.. Statistical analyses were performed using Cox regression and the Kaplan-Meier method.. We identified 2749 patients treated with sunitinib (n=1059), sorafenib (n=355), axitinib (n=359), temsirolimus (n=208), temsirolimus plus interferon-α (IFN-α) (n=208), or IFN-α (n=560), with 28% (n=781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p<0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p<0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p=0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p=0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p=0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p<0.0001). Data were analyzed retrospectively.. We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity.. In this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population.

Topics: Aged; Antineoplastic Agents; Axitinib; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma, Renal Cell; Diphosphonates; Disease-Free Survival; Female; Humans; Hypocalcemia; Imidazoles; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Pamidronate; Phenylurea Compounds; Prognosis; Pyrroles; Renal Insufficiency; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Zoledronic Acid

Temsirolimus (TEM) is a novel, water-soluble mammalian target of rapamycin (mTOR) inhibitor that has shown activity against a wide range of cancers in preclinical models, but its efficacy against colorectal cancer (CRC) has not been fully explored.. We evaluated the antitumor effect of TEM in CRC cell lines (CaR-1, HT-29, Colon26) in vitro and in vivo. In vitro, cell growth inhibition was assessed using a MTS assay. Apoptosis induction and cell cycle effects were measured using flow cytometry. Modulation of mTOR signaling was measured using immunoblotting. Antitumor activity as a single agent was evaluated in a mouse subcutaneous tumor model of CRC. The effects of adding chloroquine, an autophagy inhibitor, to TEM were evaluated in vitro and in vivo.. In vitro, TEM was effective in inhibiting the growth of two CRC cell lines with highly activated AKT, possibly through the induction of G1 cell cycle arrest via a reduction in cyclin D1 expression, whereas TEM reduced HIF-1α and VEGF in all three cell lines. In a mouse subcutaneous tumor model, TEM inhibited the growth of tumors in all cell lines, not only through direct growth inhibition but also via an anti-angiogenic effect. We also explored the effects of adding chloroquine, an autophagy inhibitor, to TEM. Chloroquine significantly potentiated the antitumor activity of TEM in vitro and in vivo. Moreover, the combination therapy triggered enhanced apoptosis, which corresponded to an increased Bax/Bcl-2 ratio.. Based on these data, we propose TEM with or without chloroquine as a new treatment option for CRC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Chloroquine; Colorectal Neoplasms; Cyclin D1; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Mice; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779).. We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1,401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts.. Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and five of six primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated.. A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Comparative Genomic Hybridization; DNA Mutational Analysis; Doxorubicin; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; MCF-7 Cells; Mice; Mutation; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases; Phosphorylation; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases; Transcriptome; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Temsirolimus acts as a mammalian target of rapamycin (mTOR)-dependent autophagic inhibitor. In order to clarify its effects and mechanisms on human salivary adenoid cystic carcinoma (ACC), we examined whether temsirolimus induced autophagy as the mTOR inhibitor in ACC, both in vitro and in vivo. In this study, MTT assay showed that the inhibition effect of temsirolimus assumed an obvious dose-response relationship on ACC-M cells, and the 50% inhibitory concentration (IC(50)) approached 20 μmol/l; numerous autophagosomes were observed by the transmission electron microscopy (TEM) in temsirolimus treatment groups; notably, expression of LC3 and Beclin1 was significantly up-regulated by temsirolimus. More importantly, the xenograft model provided further evidence of temsirolimus-induced autophagy in vivo by inhibiting mTOR activation as well as up-regulation the expression of Beclin1. These results suggest that temsirolimus could act as an mTOR inhibitor to induce autophagy in adenoid cystic carcinoma both in vitro and in vivo.

Topics: Animals; Autophagy; Carcinoma, Adenoid Cystic; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Salivary Gland Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation

Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. 3'-Deoxy-3'-(18) F-fluorothymidine ((18) F-FLT) positron emission tomography (PET) scans showed a remarkable decrease in (18) F-FLT signal in TC- and TB-treated OS-1 tumors, which was already noticeable after 1 week of treatment. No baseline uptake was observed in the OS-33 model. Both immunohistochemistry and (18) F-FLT-PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although (18) F-FLT-PET could be used for accurate and early response monitoring for temsirolimus-based therapies in the OS-1 model, we could not evaluate OS-33 tumors with this molecular imaging technique. Further research on the value of the use of (18) F-FLT-PET in this setting in osteosarcomas is warranted. Overall, these findings urge the further exploration of TC and TB treatment for osteosarcoma (and other cancer) patients.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Cell Line, Tumor; Cisplatin; Dideoxynucleosides; Female; Fluorodeoxyglucose F18; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Osteosarcoma; Positron-Emission Tomography; Protein Kinase Inhibitors; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting.. We performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS).. We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients.. Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Databases, Factual; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Practice Patterns, Physicians'; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Interstitial lung disease (ILD) is a well-known adverse effect of mammalian target of rapamycin (mTOR) inhibitors. However, it remains unknown how lung toxicities are induced by mTOR inhibitors. Here, we constructed a mouse model of mTOR inhibitor-induced ILD using temsirolimus and examined the pathogenesis of the disease. Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus (3 or 30 mg·kg(-1)·wk(-1)) or vehicle. Temsirolimus treatment increased capillary-alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space, indicating alveolar epithelial and/or endothelial injury. It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols. Alveolar macrophage depletion is thought to cause surfactant lipid accumulation. To further examine whether temsirolimus has cytotoxic and/or cytostatic effects on alveolar macrophages and alveolar epithelial cells, we performed in vitro experiments. Temsirolimus inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells. Temsirolimus treatment caused some signs of pulmonary inflammation, including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates, and an increase in lymphocytes in the bronchoalveolar lavage fluid. These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation, resulting in pulmonary inflammation. This is the first study to focus on the pathogenesis of mTOR inhibitor-induced ILD using an animal model.

Topics: Animals; Cytokines; Disease Models, Animal; Lipid Metabolism; Macrophages, Alveolar; Male; Mice; Mice, Inbred ICR; Phospholipids; Pneumonia; Pulmonary Alveoli; Pulmonary Surfactants; Sirolimus

Patients with metastatic renal cell carcinoma (mRCC) in whom first-line therapies have failed might derive clinical benefit with sequential targeted agents. Limited data are available on the efficacy and toxicity of subsequent therapies after disease progression during pazopanib therapy.. Patients with mRCC who received subsequent systemic treatment after pazopanib treatment failure were identified across 7 institutions. Pazopanib was given as first-line therapy in 28 patients and after cytokines therapy in 7 patients. Clinical outcome and toxicity analyses of 2 sequential treatment options (anti-vascular endothelial growth factor [VEGF] or mammalian target of rapamycin inhibitor [mTORi]) is presented.. Subsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient who received bevacizumab and temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n = 10), sunitinib (n = 3), bevacizumab (n = 2), cediranib (n = 4) and cabozantinib (n = 3). Patients treated with mTORi received everolimus. Median progression-free survival was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (P = .009). Overall survival (OS) was not significantly different (P = .68). Clinical benefit (including partial response and stable disease) on subsequent therapy was observed in 15 patients (64%) and 4 patients (31%) of anti-VEGF- and everolimus-treated patients, respectively (P = .021).. In this retrospective study, targeting VEGF was an effective strategy after disease progression during pazopanib treatment, although OS was not different among patients treated with VEGF or mTORi.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

A probable case of bowel perforation associated with temsirolimus use in a patient with uterine leiomyosarcoma is reported.. A 45-year-old Hispanic woman reported acute abdominal pain one day after receiving her third weekly i.v. infusion of temsirolimus, a mammalian target of rapamycin inhibitor increasingly used against a variety of cancers, including renal cell carcinoma and soft tissue sarcomas. Temsirolimus had been initiated three weeks previously in an attempt to control retroperitoneal metastases of uterine leiomyosarcoma, which had progressed despite surgical resection, six cycles of adjuvant chemotherapy, and pelvic irradiation. A computed tomography scan revealed a large pelvic mass with foci of gas, fluid collection, and other findings highly suggestive of an abscess due to bowel perforation. Application of the adverse drug reaction probability scale of Naranjo et al. in this case indicated a probable relationship between the bowel perforation and temsirolimus use; a literature search identified no other reported cases of temsirolimus-associated bowel perforation in association with uterine leiomyosarcoma. It is suspected that the patient's recent course of pelvic radiotherapy may have played a role in predisposing her to bowel perforation during temsirolimus use. While the mechanism of bowel perforations associated with temsirolimus therapy remains unclear, it is possible that due to its inhibitory effects on vascular endothelial growth factor (VEGF), temsirolimus use may result in gastrointestinal stresses and weaknesses similar to those attributed to bevacizumab, a VEGF-targeted angiogenesis inhibitor that has been linked to chemotherapy-induced bowel perforation.. A woman who recently received pelvic radiation experienced a bowel perforation after three infusions of temsirolimus for the treatment of metastatic leiomyosarcoma.

Topics: Antineoplastic Agents; Female; Humans; Intestinal Perforation; Leiomyosarcoma; Middle Aged; Pelvis; Sirolimus; TOR Serine-Threonine Kinases; Uterine Neoplasms

Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAFV600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Humans; Indoles; Melanoma; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; Skin Neoplasms; Sulfonamides; TOR Serine-Threonine Kinases; Vemurafenib

Inhibitors of the mammalian target of rapamycin (mTOR) have improved the treatment of renal cell carcinoma (RCC). However, chronic drug exposure may trigger resistance, limiting the utility of these agents. The metastatic behavior of RCC cells, susceptible (RCC(par)) or resistant (RCC(res)) to the mTOR inhibitor temsirolimus, was investigated. Adhesion to vascular endothelium or immobilized collagen and fibronectin was quantified. Chemotactic motility was evaluated with a modified Boyden chamber assay. Integrin α and β subtype receptors were analyzed by flow cytometry and Western blot analysis. The physiological relevance of the integrins was then determined by blocking studies and small interfering RNA knockdown. Adhesion to endothelial cells and to fibronectin (not to collagen) and chemotaxis were enhanced in RCC(res) compared to RCC(par). RCC(res) detached from fibronectin and motile activity further increased under retreatment with low-dosed temsirolimus. α5 integrin was diminished inside the cell and at the cell surface, whereas the β3 subtype was reduced intracellularly but elevated at the plasma membrane. In RCC(par), blocking α5 surface receptors enhanced RCC-collagen but reduced RCC-fibronectin interaction, whereas the opposite was true for RCC(res). Chemotaxis of RCC(par) but not of RCC(res) was strongly diminished by the α5 antibody. Blocking β3 significantly lowered chemotaxis with stronger effects on RCC(res), compared to RCC(par). Importantly, β3 knockdown reduced chemotaxis of RCC(par) but upregulated the motile behavior of RCC(res). Temsirolimus resistance is characterized by quantitative alterations of integrin α5 and β3 expression, coupled to functional changes of the integrin molecules, and forces a switch from RCC adhesion to RCC migration.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Drug Resistance, Neoplasm; Gene Knockdown Techniques; Humans; Integrin alpha5; Integrin beta3; Kidney Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

In a variety of neurodegenerative tauopathies including Alzheimer's disease, frontotemporal dementia and some types of Parkinson's disease, tau protein is abnormally hyperphosphorylated by several kinases and eventually aggregates to form neurofibrillary tangles, a neurotoxic pathological characteristic that closely correlates with cognitive impairments. Hence, targeting hyperphosphorylated tau protein has now been considered as a valid therapeutic approach for these neurodegenerative tauopathies. As a newly developed analog of rapamycin, temsirolimus was approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of renal cell carcinoma. Recent findings suggested that temsirolimus also provided beneficial effects in animal models of Huntington's disease and spinocerebellar ataxia type 3, two neurodegenerative diseases caused by accumulation of aberrant proteins within brain. To date, the therapeutic potentials of temsirolimus in neurodegenerative tauopathies have not been determined. Herein, we demonstrated for the first time that temsirolimus treatment effectively enhanced autophagic clearance of hyperphosphorylated tau in okadaic acid-incubated SH-SY5Y cells and in brain of P301S transgenic mice. Meanwhile, we showed that inactivation of glycogen synthase kinase-3β, the most important tau kinase, might contribute to the temsirolimus-induced reduction of tau hyperphosphorylation in these two tauopathy models. More importantly, temsirolimus administration rescued spatial learning and memory impairments in P301S transgenic mice. These findings highlight temsirolimus administration as a potential therapeutic strategy for neurodegenerative tauopathies.

Topics: Animals; Autophagy; Brain; Cell Line, Tumor; Disease Models, Animal; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Male; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Okadaic Acid; Phosphorylation; Sirolimus; Spatial Learning; Spatial Memory; tau Proteins; Tauopathies

While rapamycin and the "rapalogs" Everolimus and Temsirolimus have been approved for clinical use in the treatment of a number of forms of cancer, they have not met overarching success. Some tumors are largely refractory to rapamycin treatment, with some even undergoing an increase in growth rates. However the mechanisms by which this occurs are largely unknown. The results presented here reveal novel cell-signaling mechanisms that may lead to this resistance. The absence of TGFβ signaling results in resistance to rapamycin. Additionally, we observed that treatment of some cancer cell lines with rapamycin and its analogs not only potentiates mitogenic signaling and proliferation induced by HGF, but also stimulates the pro-survival kinase Akt. Together, the data show that the effectiveness of rapamycin treatment can be influenced by a number of factors and bring to light potential biomarkers for the prediction of responsiveness to treatment, and suggest combination therapies to optimize rapalog anticancer efficacy.

Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Proliferation; Cytostatic Agents; Everolimus; Humans; Signal Transduction; Sirolimus; Transforming Growth Factor beta

Patients with clear cell carcinoma of the ovary (OCCC) have poor survival due to resistance to standard chemotherapy. OCCC has frequent activating mutations of the PIK3CA gene. The present study was conducted to clarify the efficacy of the inhibition of the PI3K-AKT-mTOR pathway in OCCC. We used 8 OCCC cell lines and 5 ovarian serous adenocarcinoma (OSAC) cell lines. The mutation status of the PIK3CA and KRAS genes was examined by direct sequencing. The IC50 values of NVP-BEZ235 (BEZ235) and temsirolimus were determined by WST-8 assay. Protein expression levels of PI3K-AKT-mTOR pathway molecules were examined by western blotting. Cell cycle distribution was analyzed by flow cytometry. Annexin V staining was used for detecting apoptosis. We also investigated the effects of BEZ235 on OCCC tumor growth in a nude mouse xenograft model. Four of the 8 OCCC cell lines showed a PIK3CA mutation while none of the 5 OSAC cell lines showed a mutation. The IC50 values of BEZ235 for the OCCC cell lines were lower than these values for the OSAC cell lines. The IC50 value of temsirolimus was higher than BEZ235 in the OCCC cell lines. The PIK3CA mutation was more frequently noted in OCCC than OSAC cells, but the sensitivity of these cell lines to BEZ235 or temsirolimus was not related to the mutation status. pHER3 and pAkt proteins were expressed more frequently in OCCC compared with OSAC. However, protein expression levels were distributed widely, and were not related to the sensitivity. Treatment with BEZ235 suppressed expression of pAkt, although treatment with temsirolimus did not. OCCC cells exhibited G1 phase arrest after treatment with BEZ235 and apoptosis with a higher concentration of the agent. BEZ235 significantly inhibited tumor growth in mice bearing OVISE and TU-OC-1 cell tumors. The present study indicated that the PI3K-AKT-mTOR pathway is a potential target for OCCC, and that BEZ235 warrants investigation as a therapeutic agent.

Topics: Adenocarcinoma, Clear Cell; Animals; Cell Line, Tumor; Cystadenoma, Serous; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Mice; Mice, Nude; Neoplasms, Experimental; Ovarian Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Quinolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

To assess the prognostic value of clinical and biological variables in the era of targeted therapies, especially induced toxicity in patients treated for metastatic renal cell carcinoma (RCC).. A retrospective single-center study was performed in patients treated in our center from 2006 to 2012. The clinical and biological variables and toxicity data were retrospectively collected. Survival rates were calculated using the Kaplan-Meier method and compared by the Log-Rank test. Multivariate analysis was also performed using the Cox model.. One hundred and two patients were included, with a median follow-up of 20 months. The median overall survival (OS) was 21 months, and 6 months for the progression free survival (PFS). As expected, the variables included in the Mozter prognostic score had a significant impact on OS (P < 0.0001) and PFS (P < 0.0001). However, hypoalbuminemia (P < 0.0001), brain metastasis (P = 0.003) and the absence of nephrectomy (P < 0.0001) were found as poor prognosis factors for OS. In addition, severe toxicity (grade 3-4) was significantly associated with higher OS (P < 0.0001) and PFS (P = 0.0003) and appeared as an independent factor in multivariate analysis for OS (P = 0.02) and PFS (P = 0.01).. Severe toxicity induced by targeted therapies was found as a prognostic factor increasing significantly the survival. Further studies are needed to assess the real value of this factor in the development of sequential therapies for the treatment of RCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Prognosis; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate

Perivascular epithelioid cell tumors (PEComas) are rare tumors driven by tuberous sclerosis complex gene mutations causing up-regulation of mTOR. We report the outcome of ten consecutive patients treated with sirolimus or temsirolimus.. A retrospective analysis was performed on patients seen between 2007 and 2013. Demographic and treatment data were collected and radiological response was assessed.. Ten patients were investigated, eight females, with median age of 47.5 years. Nine patients received sirolimus, one temsirolimus. The median treatment duration was 128 (range=7-1,366 days). Temsirolimus was given at 25 mg IV weekly and median starting dose of sirolimus was 3 mg daily. Seven patients were evaluable for response by RECIST: 5 showed partial response (50%), 1 stable disease (10%) and 1 progressive disease (10%). Two patients progressed rapidly on treatment. One patient stopped due to grade 3 hyperlipidaemia although CT scan shows maintained response. Three patients continue on treatment while the remainder stopped due to disease progression.. Our study confirms that mTOR inhibition with sirolimus/temsirolimus is well-tolerated with good radiological responses, albeit short-lived, and supports its use in PEComas.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Perivascular Epithelioid Cell Neoplasms; Retrospective Studies; Sirolimus; Treatment Outcome

Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies.. PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials.

Topics: Autophagy; Cell Line, Tumor; Gene Deletion; Human Umbilical Vein Endothelial Cells; Humans; Insulin-Like Growth Factor I; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptor, IGF Type 1; Sarcoma, Ewing; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Second-line targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs). This study compares the effectiveness of these therapies in a multi-practice chart review and synthesizes the findings with those of a similarly designed study.. Medical oncologists/hematologists (N = 36) were recruited to review charts for patients aged ≥18 years, received a first-line TKI and initiated second-line targeted therapy in 2010 or later. The primary outcome was time from second-line initiation to treatment failure (TTF; discontinuation, physician-assessed progression, or death, whichever occurred first). TTF was compared among patients receiving second-line everolimus (EVE), temsirolimus (TEM), or TKI as a class, using a Cox proportional hazards model adjusting for type of initial TKI and response, histological subtype, performance status, and sites of metastasis. Hazard ratios (HRs) for TTF were pooled, in a meta-analysis, with previously reported HRs for progression-free survival from a chart review with a similar design.. A total of 138, 64 and 79 patients received second-line therapy with EVE, TEM or a TKI, respectively. Adjusting for baseline characteristics, EVE was associated with numerical, but not statistically significant, reductions of 28% (HR = 0.72; 95% CI [0.45-1.16]) and 26% (HR = 0.74; 95% CI [0.48-1.15]) in the hazard of TTF compared to TEM and TKI, respectively. After pooling the HRs from both studies, EVE was associated with significantly reduced hazards of TTF compared to TEM and TKI (HR = 0.73; 95% CI [0.57-0.93]; and HR = 0.75; 95% CI [0.57-0.98], respectively).. LIMITATIONS include retrospective analyses with possible missing or erroneous chart data, confounding of unobserved factors due to non-randomization, and limited data for axitinib during the study period.. In pooled results from two independent multi-practice chart reviews of second-line mRCC treatment, EVE was associated with significantly reduced hazards of treatment failure compared to TEM and to TKIs as a class.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; Sirolimus; Treatment Failure; United States

Triple-negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive disease. They have a high rate of relapse and often develop resistance to standard chemotherapy. Many TNBCs have elevated epidermal growth factor receptor (EGFR) but are resistant to EGFR inhibitors as monotherapy. In this study, we sought to find a combination therapy that could sensitize TNBC to EGFR inhibitors. Phospho-mass spectrometry was performed on the TNBC cell line, BT20, treated with 0.5 μM gefitinib. Immunoblotting measured protein levels and phosphorylation. Colony formation and growth assays analyzed the treatment on cell proliferation, while MTT assays determined the synergistic effect of inhibitor combination. A Dual-Luciferase reporter gene plasmid measured translation. All statistical analysis was done on CalucuSyn and GraphPad Prism using ANOVAs. Phospho-proteomics identified the mTOR pathway to be of interest in EGFR inhibitor resistance. In our studies, combining gefitinib and temsirolimus decreased cell growth and survival in a synergistic manner. Our data identified eIF4B, as a potentially key fragile point in EGFR and mTOR inhibitor synergy. Decreased eIF4B phosphorylation correlated with drops in growth, viability, clonogenic survival, and cap-dependent translation. Taken together, these data suggest EGFR and mTOR inhibitors abrogate growth, viability, and survival via disruption of eIF4B phosphorylation leading to decreased translation in TNBC cell lines. Further, including an mTOR inhibitor along with an EGFR inhibitor in TNBC with increased EGFR expression should be further explored. Additionally, translational regulation may play an important role in regulating EGFR and mTOR inhibitor synergy and warrant further investigation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Synergism; ErbB Receptors; Eukaryotic Initiation Factors; Female; Gefitinib; HEK293 Cells; Humans; Phosphorylation; Protein Kinase Inhibitors; Quinazolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms

Interstitial lung disease (ILD) is an adverse event which occurs also during targeted treatment of patients with metastatic renal cell carcinoma (mRCC). Experiences on ILD-management in mRCC remain limited. mRCC patients treated with everolimus, temsirolimus, or sunitinib at three centres from January 2006 until December 2009 were analysed, retrospectively. Medical records and imaging studies, as well as clinical course, the incidence, diagnostic measures, treatment, and outcome of ILD were assessed. Twenty-six ILD patients (11 %) were identified out of 237 mRCC patients. Median treatment until ILD-diagnosis was 3.8 (range: 1-21.5) months. The ILD-frequency was 2.7 % (n = 6/226) during sunitinib therapy and 19.8 % (n = 20/101) during m-TOR-inhibitor treatment. Cough was the prevailing symptom (69.2 %, n = 18). Bronchoalveolar lavage reviled often lymphocytic (42.9 %, n = 6/14) or eosinophilic cellularity (28.6 %, n = 4/14). Dose reduction (42.3 %, n = 11), treatment interruption (46.2 %, n = 12) or termination (23.1 %, n = 6), and steroid application (34.6 %, n = 9) were common measures in ILD. Interestingly, eosinophilic ILD required pulsed steroids. Improvement occurred in 73.7 % of symptomatic patients. Continuation of targeted therapies was warranted in 65.4 % of ILD patients. No patient died from ILD. ILD during targeted mRCC treatment is common, and supportive measures should be adapted to the clinical course, and potentially in dependence of BAL findings. Re-exposure to targeted therapies appears feasible.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Pyrroles; Retrospective Studies; Risk Factors; Sirolimus; Sunitinib

Epstein-Barr virus (EBV) infects B cells, as well as T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoid malignancies. In various tumor cells, mTOR performs an essential function together with Akt with regard to cell growth. We investigated the effects of mTOR inhibitors on EBV-associated T- and NK-cell lymphomas.. We investigated the Akt/mTOR activation pathway in EBV-positive and -negative T- and NK-cell lines (SNT13, SNT16, Jurkat, SNK6, KAI3, and KHYG1). We evaluated the antitumor effects of mTOR inhibitors (rapamycin and its analogue, CCI-779) against these cell lines in culture and in a murine xenograft model that was established by subcutaneous injection of SNK6 cells into NOG mice.. All EBV-positive and -negative T- and NK-cell lines tested displayed activation of the Akt/mTOR pathway, and treatment with mTOR inhibitors suppressed mTOR activation. The inhibitors induced G1 cell-cycle arrest and inhibited cell proliferation in T- and NK-cell lines. Overall, T cell lines were more sensitive to rapamycin, but there were no significant differences between EBV-positive and -negative cell lines. Treatment with rapamycin did not affect lytic or latent EBV gene expression. Intraperitoneal treatment with CCI-779 significantly inhibited the growth of established tumors in NOG mice and reduced the EBV load in peripheral blood.. These results suggest that inhibition of mTOR signaling is a promising new strategy for improving treatment of EBV-associated T- and NK-cell lymphoma.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Epstein-Barr Virus Infections; G1 Phase Cell Cycle Checkpoints; Herpesvirus 4, Human; Humans; Jurkat Cells; Killer Cells, Natural; Lymphoma, T-Cell; Mice; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases

How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Brain Neoplasms; Cell Cycle; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Profiling; Glioma; Immunohistochemistry; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Neural Stem Cells; Neurofibromin 1; Oligodendroglia; Oligonucleotide Array Sequence Analysis; Sirolimus; Tamoxifen; Tumor Cells, Cultured; Tumor Suppressor Protein p53

The standard of care for head and neck cancer typically includes surgical resection of the tumor followed by targeted head and neck radiation. However depending on tumor location and stage, some cases may not require surgical resection while others may be treated with chemoradiation. Unfortunately, these radiation treatments cause chronic negative side effects for patients. These side effects are associated with damage to surrounding normal salivary gland tissue and include xerostomia, changes in taste and malnutrition. The underlying mechanisms of chronic radiation-induced salivary gland dysfunction are unknown, however, in rodent models persistently elevated proliferation is correlated with reduced stimulated salivary flow. The rapalogue, CCI-779, has been used in other cell systems to induce autophagy and reduce proliferation, therefore the aim of this study was to determine if CCI-779 could be utilized to ameliorate chronic radiation-induced salivary gland dysfunction. Four to six week old Atg5f/f; Aqp5-Cre, Atg5+/+; Aqp5-Cre and FVB mice were treated with targeted head and neck radiation. FVB mice were treated with CCI-779, chloroquine, or DMSO post-radiation. Stimulated salivary flow rates were determined and parotid and submandibular salivary gland tissues were collected for analyses. Mice with a defect in autophagy, via a conditional knockout of Atg5 in the salivary glands, display increased compensatory proliferation in the acinar cell compartment and hypertrophy at 24-72 hours following radiation. FVB mice treated with post-therapy CCI-779 have significant improvements in salivary gland physiology as determined by stimulated salivary flow rates, proliferation indices and amylase production and secretion. Consequently, post-radiation use of CCI-779 allows for improvement of salivary gland function and reestablishment of glandular homeostasis. As CCI-779 is already FDA approved for other uses, it could have a secondary use to alleviate the chronic side effects in head and neck cancer patients who have completed anti-tumor therapy.

Topics: Amylases; Animals; Autophagy; Autophagy-Related Protein 5; Cell Proliferation; Head and Neck Neoplasms; Mice; Microtubule-Associated Proteins; Parotid Gland; Recovery of Function; Signal Transduction; Sirolimus; Submandibular Gland; Time Factors; TOR Serine-Threonine Kinases

To evaluate the mTORC1 (mammalian target of rapamycin complex 1) pathway in meningiomas and to explore mTORC1 as a therapeutic target in meningioma cell lines and mouse models.. Tissue microarrays (53 meningiomas of all WHO grades) were stained for phosphorylated polypeptides of mTOR, Akt, and the mTORC1 targets 4EBP1 and p70S6K, the latter being the consensus marker for mTORC1 activity. Expression of proteins and mRNAs was assessed by Western blotting and real-time PCR in 25 tumors. Cell lines Ben-Men-1 (benign), IOMM-Lee and KT21 (malignant), and pairs of merlin-positive or -negative meningioma cells were used to assess sensitivity toward mTORC1 inhibitors in methyl-tetrazolium and bromodeoxyuridine (BrdUrd) assays. The effect of temsirolimus (20 mg/kg daily) on tumor weight or MRI-estimated tumor volume was tested by treatment of eight nude mice (vs. 7 controls) carrying subcutaneous IOMM-Lee xenografts, or of eight (5) mice xenotransplanted intracranially with IOMM-Lee (KT21) cells in comparison to eight (5) untreated controls.. All components of the mTORC1 pathway were expressed and activated in meningiomas, independent of their WHO grade. A significant dosage-dependent growth inhibition by temsirolimus and everolimus was observed in all cell lines. It was slightly diminished by merlin loss. In the orthotopic and subcutaneous xenograft models, temsirolimus treatment resulted in about 70% growth reduction of tumors (P < 0.01), which was paralleled by reduction of Ki67 mitotic index (P < 0.05) and reduction of mTORC1 activity (p70S6K phosphorylation) within the tumors.. mTORC1 inhibitors suppress meningioma growth in mouse models, although the present study did not measure survival.

Topics: Animals; Apoptosis; Blotting, Western; Cell Adhesion; Cell Proliferation; Disease Models, Animal; Genes, Neurofibromatosis 2; Humans; Immunoenzyme Techniques; Male; Mechanistic Target of Rapamycin Complex 1; Meningeal Neoplasms; Meningioma; Mice; Mice, Nude; Multiprotein Complexes; Neoplasm Grading; Protein Kinase Inhibitors; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Docetaxel and temsirolimus are some of the most used drugs in a wide range of solid tumors. In preclinical studies, mTOR inhibitors such as temsirolimus have demonstrated synergistic cytotoxic effects with taxanes providing the rationale for combination studies. These anticancer agents exhibit a narrow therapeutic concentration range and due to their high inter- and intra-individual pharmacokinetic variability, therapeutic dose monitoring by highly sensitive methods as LC-MS/MS are important for clinical research. Therefore, the aim of this study was to develop and validate a sensitive, fast and convenient method for the simultaneous identification and quantification of docetaxel, temsirolimus and its main metabolite, sirolimus, using paclitaxel, another anticancer drug, as the internal standard. These analytes were quantified by an integrated online solid phase extraction-high performance liquid chromatography-tandem mass spectrometry (SPE-HPLC-MS/MS) system. Separation was performed on a Zorbax eclipse XDB-C8 (150mm×4.6mm, 5μm) column. The mass spectrometer tandem quadruple detector was equipped with jet stream electrospray ionization, monitored in multiple reactions monitoring (MRM) and operated in positive mode. A combination of protein precipitation with methanol/zinc sulphate (70:30) (v/v) and online SPE using a Zorbax eclipse plus C8 (12.5mm×4.6mm, 5μm) cartridge was used to extract the compounds. This method allows the use of the same reagents, sample treatment and analytical technique independently of whether the samples are whole blood or plasma. The method has been successfully validated and applied to real samples. It is a suitable method for dose adjustment and for evaluating potential drug interactions during combined treatments.

Topics: Antineoplastic Agents; Chromatography, High Pressure Liquid; Docetaxel; Humans; Sensitivity and Specificity; Sirolimus; Solid Phase Extraction; Tandem Mass Spectrometry; Taxoids

To evaluate the outcomes following targeted therapies in the management of metastatic renal cell carcinoma (mRCC), through the study of overall survival (OS) and progression-free (PFS).. We retrospectively included 78 patients treated with targeted therapies for mRCC at the Paul Papin Cancer Institute from 2004 to 2009. Overall survival (OS), progression free survival (PFS), response to treatment, occurrence of grade III and IV side effects, were analyzed following first and second line treatments.. Median follow-up was 33 months [5-236], and 41 patients died (52.6%). Median OS was 36 months [95% CI 29-43]. The median PFS was 14 months [95% CI 6.71-21.29] for sunitinib, 38 months [95% CI 11.41-64.59] for bevacizumab with interferon (IFN), and 8 months [95% CI 0-17.03] for IFN alone. A partial reduction, stabilization or increase in tumor size was observed for 19.2%, 47.4% and 25.6% of cases. A second line treatment was given for 53 patients. They received either sunitinib (n=20, 37.8%), bevacizumab with IFN (n=7, 13.2%), sorafenib (n=17, 32.2%), temsirolimus (n=3, 5.6%) or other molecules (n=6 11.2%). Grade III or IV side effects were observed for 14.1%, 28.3% and 18.2% of the patients following first, second and third line treatment, respectively.. Outcomes of targeted therapies in our center upheld the literature data. These therapies allow a benefit survival versus immunotherapy, with sometimes large side-effect.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Indoles; Interferons; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Analysis; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Female; Humans; Male; Sarcoma; Sirolimus

To evaluate first-generation rapamycin analogs (everolimus, temsirolimus, and rapamycin) and second-generation drugs inhibiting mTOR kinase (AZD-8055), PI3K (BKM-120) or both (BEZ-235 and GDC-0980) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) cells characterized for acquired resistance to sorafenib or sunitinib.. Anti-proliferative (MTT assay) and cell signaling (Western blot) effects of rapamycin analogs (1-20 μM) and second-generation drugs (0.03-20.0 μM) were assessed in human HCC SK-HEP1, RCC 786-0, and sorafenib- (SK-Sora) or sunitinib-resistant (786-Suni) cells.. In SK-HEP1 cells displaying high PTEN and Bcl2 expression, rapamycin analogs had poor anti-proliferative effects. However, SK-Sora cells were more sensitive to rapamycin analogs (≥1 μM) than SK-HEP1 cells. In 786-0 cells, lacking PTEN and Bcl2 expression, ≥1 μM rapamycin analogs blocked mTORC1 signaling, transiently activated Akt, and inhibited cell proliferation. Protracted sunitinib exposure in 786-Suni cells yielded an increase in p27 expression and a decreased sensitivity to rapamycin analogs, although mTORC1 function could be inhibited with rapamycin analogs. Second-generation drugs induced more potent growth inhibition than rapamycin analogs at concentrations >0.03 μM in parental cells, SK-Sora, and 786-Suni cells. Growth inhibitory concentrations of these new drugs also blocked mTORC1 downstream targets.. Rapamycin analogs inhibited mTORC1 downstream targets and yielded anti-proliferative effects in HCC and RCC cells. Second-generation drugs also appeared to be potent inhibitors of mTORC1 signaling; however, they appeared to be far more potent in inhibiting cellular proliferation in parental HCC and RCC cells and in cells developing resistance to sorafenib or sunitinib.

Topics: Aminopyridines; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Hepatocellular; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Everolimus; Humans; Imidazoles; Indoles; Kidney Neoplasms; Liver Neoplasms; Mechanistic Target of Rapamycin Complex 1; Morpholines; Multiprotein Complexes; Niacinamide; Phenylurea Compounds; Phosphoinositide-3 Kinase Inhibitors; Pyrimidines; Pyrroles; Quinolines; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases

Sequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. The goal of this study was to evaluate these questions in a large series of pts treated in our institution.. Data from all mRCC patients treated at the IGR from 2005 to 2009 with first line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mammalian target of rapamycin - mTOR)) were analysed. Only patients with subsequent follow-up have been included in this analysis. Patients were defined as 'non-eligible' for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response) or (iii) if they refused a second line treatment.. 251 patients, median age 60 years, median follow-up 20.2 months were treated with targeted therapy with a median overall survival (OS) of 25.8 months. Median OS with SU (127), SO (60) or B (61) were 26.3, 16.4 and 32.5 months respectively. Only three patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. Memorial Sloan-Kettering Cancer Centre (MSKCC) classification (P=0.02) and first line agent (P=0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of performance status score (PS)=0 compared to SO (53%) and SU (48%) (P=0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8 months for a tyrosine kinase inhibitor (TKI) (n=98; 75%) and 16.6 months for an mTOR (n=32; 42%) (P=0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively.. The median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2 years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for second line treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Cardiovascular Diseases; Disease Progression; Drug Administration Schedule; Everolimus; Female; Follow-Up Studies; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome; Young Adult

Colorectal cancer is the second leading cause of cancer-related deaths. Drug resistance and/or off-target toxicity against normal cells limit the effectiveness of current chemotherapies for the treatment of colorectal cancer. In the current study, we studied the potential cytotoxic effects of short-chain and cell-permeable C6 ceramide in cultured colorectal cancer HT-29 cells and focused on the underlying mechanisms. We observed that C6 ceramide-induced HT-29 cell death and growth inhibition in a dose- and time-dependent manner. However, no significant apoptosis was observed in C6 ceramide-treated HT-29 cells. Our data support that autophagy contributed to C6 ceramide-induced cytotoxic effects, as autophagy inhibitors, 3-methyladenine (3-MA) and hydroxychloroquine, inhibited C6 ceramide's effect; however, autophagy activators, everolimus (RAD001) and temsirolimus, mimicked C6 ceramide effects and induced HT-29 cell death. Further, we indentified that AMP-activated protein kinase (AMPK)/Ulk1 signaling was required for autophagy induction by C6 ceramide, and AMPK silencing by a specific short hairpin RNA suppressed C6 ceramide-induced autophagy and cytotoxic effects. Reversely, forced activation of AMPK by its activator AICAR or by genetic manipulation caused autophagic death in HT-29 cells, which was inhibited by 3-MA. Our results suggest that autophagy, but not apoptosis, is a major contributor for C6 ceramide-induced cytotoxic effects in HT-29 cells, and activation of AMPK/Ulk1 is required for the process.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Autophagy; Autophagy-Related Protein-1 Homolog; Cell Survival; Ceramides; Colorectal Neoplasms; Enzyme Activation; Everolimus; HCT116 Cells; HT29 Cells; Humans; Intracellular Signaling Peptides and Proteins; Protein Serine-Threonine Kinases; Ribonucleotides; Signal Transduction; Sirolimus

We present a case report of long-term response with temsirolimus in cytokine refractory metastatic renal cell carcinoma (RCC). A 74-year-old Japanese man was diagnosed with advanced RCC in November 2007 and enrolled in a phase II study to examine the safety and efficacy of temsirolimus in East Asian patients with metastatic RCC. He achieved a partial response 12 months after starting treatment with temsirolimus followed by stable disease for 39 months. The most notable toxicity was grade 3 pericardial effusion, which gradually increased 2 years after treatment start until discontinuation of the trial resulting in pericardial tamponade, grade 3 hypoxia associated with chronic obstructive pulmonary disease (COPD), which he had before the trial, and latent interstitial pneumonia. The cease of temsirolimus led to improvement of interstitial pneumonia while the target lesion progressed. He died of progressive COPD and latent interstitial pneumonia 4 months after discontinuing temsirolimus. To our knowledge, he lived the longest in East Asian populations since starting temsirolimus.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Humans; Kidney Neoplasms; Male; Sirolimus

Endometrial cancer, one of the most common gynecologic malignancies, is increasing in Japan, nearly doubling over the last decade. High-grade disease patients are often resistant to conventional chemotherapy with platinum agents; therefore, discovery of efficacious new drugs in this setting is required to benefit chemorefractory cases. The 50% growth-inhibitory (GI50) concentration of 27 clinically relevant drugs was measured in the NCI60 panel of cell lines. Gene expression data were analyzed using Bayesian binary regression, to first generate a response signature for each drug and then to calculate individual susceptibility scores using in vivo endometrial cancer data (GSE2109; http://www.ncbi.nlm.nih.gov/geo) and in vitro data (GSE25458), as well as to identify candidate drugs for chemorefractory cases. Using these candidates, cell proliferation, apoptosis and caspase assays were performed in vitro. The tumor growth-inhibitory effect of the candidate was also assessed in vivo using nude mice. Through microarray analysis, fludarabine and temsirolimus showed higher susceptibility scores in high-grade cases compared to cisplatin, doxorubicin and paclitaxel. Fludarabine significantly inhibited cell proliferation and increased apoptosis in the cisplatin-resistant endometrial cancer cell line, HEC1A, relative to HEC50B (p < 0.001). Fludarabine treatment also enhanced caspase-3/7 activity in HEC1A relative to HEC50B cells (p < 0.001), and inhibited the growth of HEC1A xenograft tumors relative to cisplatin (p < 0.05). These results support that identification and use of genomic signatures can lead to identification of new therapeutic candidates that may prove beneficial to chemoresistant cases. Fludarabine may be useful in targeting high-grade, chemorefractory endometrial cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bayes Theorem; Biomarkers, Tumor; Blotting, Western; Carboplatin; Cell Proliferation; Cisplatin; Doxorubicin; Drug Resistance, Neoplasm; Endometrial Neoplasms; Female; Follow-Up Studies; Gene Expression Profiling; Humans; Middle Aged; Neoplasm Grading; Neoplasm Staging; Oligonucleotide Array Sequence Analysis; Paclitaxel; Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; Survival Rate; Tumor Cells, Cultured; Vidarabine

We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens.. Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus.. Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo.. Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Synergism; Female; Gene Expression; Humans; Indazoles; Indoles; Kidney Neoplasms; Mice; Mice, Nude; Molecular Targeted Therapy; Pyrimidines; Pyrroles; Sirolimus; Stearoyl-CoA Desaturase; Sulfonamides; Sunitinib; Tumor Burden; Up-Regulation; Xenograft Model Antitumor Assays

To investigate the efficacy and safety of zoledronic acid (ZA) combined with targeted therapy (TT).. A retrospective study was performed in patients with metastatic renal cell carcinoma treated with ZA and TT.. Twenty-one patients received ZA and TT to prevent skeletal-related events and no pretherapy oral and maxillofacial (OM) examination (cohort A). Six patients (29%) developed osteonecrosis of the jaw (ONJ), which was observed only in patients receiving sunitinib and ZA. Sixteen patients received TT and ZA for hypercalcemia and no pretherapy OM examination (cohort B). In these patients, no ONJ was observed. Nine patients received ZA and TT and pretherapy OM examination (cohort C). One patient (11%) developed ONJ during sunitinib and ZA treatment. Mean skeletal morbidity rates were 0.8 for cohort A and 1.2 for cohort C. In the combined cohort (A plus C; n = 30), 47% developed skeletal-related events, 7% pathologic fracture, 7% medullary compression, and 37% progression of bone metastases. Patients who developed ONJ had a significantly improved median survival of 31.6 months compared with 14.5 months in patients without ONJ (P = .039).. The combination of ZA and TT resulted in high, clinically meaningful activity. ONJ may be exacerbated by concomitant ZA and sunitinib. Regular OM examinations before and during treatment are recommended.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma, Renal Cell; Cohort Studies; Diphosphonates; Everolimus; Female; Follow-Up Studies; Fractures, Spontaneous; Humans; Imidazoles; Indazoles; Indoles; Interleukin-2; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Radiography, Panoramic; Retrospective Studies; Sirolimus; Sorafenib; Spinal Cord Compression; Sulfonamides; Sunitinib; Survival Rate; Zoledronic Acid

Mammalian target of rapamycine (mTOR) inhibitors are being increasingly prescribed as antitumoural drugs, and associated adverse cutaneous effects are frequent but poorly described. The aim of this study was to describe such adverse effects and to assess the quality of life of patients experiencing them.. Over a period of 18 months, 18 patients treated with mTOR inhibitors for renal carcinoma were included and 77 dermatological examinations performed. Wherever a cutaneous adverse event was present, quality of life was evaluated using the Skindex 30 questionnaire.. Fifteen of the 18 patients included presented adverse cutaneous events, consisting of buccal ulcers (61.1%), xerosis (55.5%), distal onycholysis (50%), acneiform eruption (38.8%), paronychia (22.2%) and pruritus (22.2%). Buccal ulcerations and perionyxis had an especially marked impact on quality of life, which was greatest in terms of physical score (19%), followed by emotional (9%) and functional (6%) scores.. Cutaneous adverse effects of mTOR inhibitors are frequent and have a considerable impact on quality of life, particularly as regards physical scores. Dermatological examination appears useful to allow early management of cutaneous adverse effects and improve the quality of life of these patients.

Topics: Acneiform Eruptions; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Eruptions; Emotions; Everolimus; Female; Humans; Ichthyosis; Kidney Neoplasms; Male; Middle Aged; Onycholysis; Paronychia; Prospective Studies; Pruritus; Quality of Life; Severity of Illness Index; Sirolimus; Stomatitis, Aphthous; TOR Serine-Threonine Kinases

The outcomes and prognosis of patients with brain metastases from advanced renal cell carcinoma (RCC) are not well characterized in the targeted-therapy era.. Data from patients with metastatic RCC (mRCC) and brain metastases treated with targeted therapy were collected through the International Metastatic Renal Cell Carcinoma Database Consortium from 7 cancer centers.. Overall, 106 (15%) of 705 patients with mRCC had brain metastases. Forty-seven patients had brain metastases at the start of first-line anti-vascular endothelial growth factor therapy, and the rest developed metastases during follow-up. Of the patients with brain metastases, 12%, 42% and 29% were in the favorable, intermediate, and poor prognosis groups, respectively, per the Heng criteria. Ninety percent had cerebral metastases, 17% had cerebellar metastases, 37% had a Karnofsky performance status (KPS) <80%, and 80% had neurologic symptoms at presentation. The median largest size and number of brain metastases was 1.8 cm (range, 0.2-6.6 cm) and one (range, 1 to innumerable), respectively. The patients were treated with sunitinib (n = 77), sorafenib (n = 23), bevacizumab (n = 5), and temsirolimus (n = 1). Local disease treatment included whole brain radiotherapy (81%), stereotactic radiosurgery (25%), and neurosurgery (25%). On multivariable analysis, KPS < 80%, diagnosis to treatment with targeted therapy <1 year, and a higher number of brain metastases (>4) was associated with worse survival from the time of diagnosis with brain metastases.. Patients with brain metastases from RCC are unlikely to be in the favorable risk group. KPS at the start of therapy, diagnosis to treatment time, and the number of brain metastases are prognostic factors for overall survival.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Brain Neoplasms; Carcinoma, Renal Cell; Databases, Factual; Humans; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Survival; Treatment Outcome

Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.. Here, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.. Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.

Topics: Adult; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Sirolimus; Treatment Outcome

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is a critical problem in the treatment of EGFR mutant lung cancer. Several mechanisms, including bypass signaling by hepatocyte growth factor (HGF)-triggered Met activation, are implicated as mediators of resistance. The mammalian target of rapamycin (mTOR), is a downstream conduit of EGFR and MET signaling, and is thus considered a therapeutically attractive target in the treatment of various types of cancers. The purpose of this study was to examine whether 2 clinically approved mTOR inhibitors, temsirolimus and everolimus, overcome HGF-dependent resistance to EGFR-TKIs in EGFR mutant lung cancer cells. Both temsirolimus and everolimus inhibited the phosphorylation of p70S6K and 4E-BP1, which are downstream targets of the mTOR pathway, and reduced the viability of EGFR mutant lung cancer cells, PC-9, and HCC827, even in the presence of HGF in vitro. In a xenograft model, temsirolimus suppressed the growth of PC-9 cells overexpressing the HGF-gene; this was associated with suppression of the mTOR signaling pathway and tumor angiogenesis. In contrast, erlotinib did not suppress this signaling pathway or tumor growth. Multiple mechanisms, including the inhibition of vascular endothelial growth factor production by tumor cells and suppression of endothelial cell viability, contribute to the anti-angiogenic effect of temsirolimus. These findings indicate that mTOR inhibitors may be useful for controlling HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer, and they provide the rationale for clinical trials of mTOR inhibitors in patients stratified by EGFR mutation and HGF expression status.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; ErbB Receptors; Everolimus; Hepatocyte Growth Factor; Humans; Lung Neoplasms; Mice; Mutation; Neovascularization, Pathologic; Phosphorylation; Protein Kinase Inhibitors; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

To determine if mammalian target of rapamycin (mTOR) inhibitor (everolimus or temsirolimus) rechallenge in the third- or fourth-line setting after sequential use of a vascular endothelial growth factor receptor (VEGF)-targeted agent and an mTOR inhibitor is a feasible and effective treatment strategy in patients with metastatic renal cell carcinoma (mRCC).. Patients who received a VEGF-targeted agent, an mTOR inhibitor and rechallenge with a second mTOR inhibitor at 2 institutions (Hôpital Européen Georges-Pompidou and Vienna Medical School) between 30 March 2001 and 15 September 2011 were included. Analyses of radiographic images were performed according to the Response Evaluation Criteria in Solid Tumors, version 1.0, to determine the objective response rate and treatment duration (TD).. Twelve patients met the inclusion criteria. Following 1 or 2 VEGF receptor-tyrosine kinase inhibitors, 7 patients firstly received everolimus and 5 patients received temsirolimus. Irrespective of treatment sequence, 6 of 12 patients (50%) responded to everolimus and 4 of 12 patients (33%) responded to temsirolimus; 3 patients (25%) did not respond to either. Median TDs (95% confidence interval) for everolimus → temsirolimus and temsirolimus → everolimus sequences were 10.3 months (8.8-19.2 months) and 5.8 months (2.9-19.3 months), respectively.. Despite the limited number of patients, this highlights the feasibility of utilizing mTOR rechallenge as an integral part of sequential treatment strategies in mRCC.

Topics: Aged; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Hepatic arterial infusion (HAI) of specific anti-tumor drugs can be more effective compared with systemic drug application. Herein, we studied whether HAI of temsirolimus is effective to inhibit tumor growth of colorectal liver metastases after liver resection.. Twenty-four Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats were randomized to four groups and underwent subcapsular implantation of CC531 colorectal cancer cells in the left liver lobe. In two groups, a 70% liver resection (Phx) was performed simultaneously. After 10 d, animals received either a HAI of temsirolimus (CCI-779) or saline solution (controls). Tumor growth was determined on d 10 and 13 using three-dimensional ultrasound. On d 13, tumor tissue was removed for histologic and immunohistochemical analysis.. Sham controls revealed a tumor growth of ∼40% from d 10 to d 13. HAI of temsirolimus completely inhibited this tumor growth. Controls with Phx showed a tumor growth of >60%. In contrast, HAI of temsirolimus in Phx animals did not only inhibit tumor growth but was even capable of decreasing the tumor size by ∼8%. Immunohistochemical analysis of the tumors showed a decreased proliferation rate and an increased cleaved caspase-3 activity, which was associated with a significant reduction of platelet endothelial cell adhesion molecule (PECAM)-1-positive cells after HAI of temsirolimus.. HAI of temsirolimus inhibits tumor growth of CC531 colorectal liver metastases even if a growth-stimulating procedure like Phx is performed. Inhibition of tumor growth is provided by a decrease of tumor vascularization associated with an inhibition of tumor cell proliferation and an induction of tumor cell apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Hepatic Artery; Liver; Liver Neoplasms, Experimental; Liver Regeneration; Male; Neovascularization, Pathologic; Random Allocation; Rats; Rats, Wistar; Sirolimus

Neuroendocrine tumors of the gastroenteropancreatic tract remain a difficult array of neoplasia to treat. Treatment of advanced and metastatic gastroenteropancreatic neuroendocrine tumors has traditionally been difficult with few systemic treatment options. In 2011, two new targeted therapies, everolimus and sunitinib were approved for treatment of pancreatic neuroendocrine tumor. The approval of these agents led to an enhanced interest in exploring novel agents. This can be evidenced by the fact that this is the first year that ASCO assembled related abstracts under a separate title of neuroendocrine tumor. The annual American Society of Clinical Oncology (ASCO) conference in 2013 presented four abstracts (#4030, #4031, #4032, #4136) that shed light on new therapeutic options that help target the unique pathways involved in these neuroendocrine malignancies.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Everolimus; Humans; Indoles; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pyrroles; Sirolimus; Stomach Neoplasms; Sunitinib; Treatment Outcome

Neuroendocrine tumors of the pancreas (pNETs) are classified on the basis of their differentiation as well as the functional status. Current treatment options for non resectable disease include everolimus, sunitinib, somatostatin analogs and chemotherapy. A number of trials with novel compounds and drug combinations were reported at the recent ASCO Annual Meeting. Pasireotide is a novel somatostatin analog with broader affinity for the somatostatin receptors compared to the traditional octreotide and lantreotide and it appears to be safe in patients with pNETs according to a phase I study (Abstract #e15126). The combination of octreotide with everolimus showed promising response rate and progression free survival in a phase II study (Abstract #4136). In another phase II study, the AKT inhibitor MK-2206 was well tolerated with moderate efficacy (Abstract #e15133). Last but not least, we discuss the updated data from a phase II study that used the combination of temsirolimus with bevacizumab in patients with advanced pNETs (Abstract #4032).

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Everolimus; Heterocyclic Compounds, 3-Ring; Humans; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

Burkitt leukemia/lymphoma is a major subtype of aggressive B-cell lymphoma. Biological targeted therapies on this disease need to be further investigated and may help to improve the clinical outcome of the patients.. This study examined the anti-tumor activity of the histone deacetylases (HDAC) inhibitor valproic acid (VPA) combined with the mammalian target of rapamycin (MTOR) inhibitor temsirolimus in Burkitt leukemia/lymphoma cell lines, as well as in primary tumor cells and a murine xenograft model.. Co-treatment of VPA and temsirolimus synergistically inhibited the tumor cell growth and triggered the autophagic cell death, with a significant inhibition of MTOR signaling and MYC oncoprotein. Functioned as a class I HDAC inhibitor, VPA potentiated the effect of temsirolimus on autophagy through inhibiting HDAC1. Molecular silencing of HDAC1 using small interfering RNA (siRNA) attenuated VPA-mediated regulation of CDKN1A, CDKN1B and LC3-I/II, regression of tumor cell growth and induction of autophagy. Meanwhile, VPA counteracted temsirolimus-induced AKT activation via HDAC3 inhibition. HDAC3 siRNA abrogated the ability of VPA to modulate AKT phosphorylation, to suppress tumor cell growth and to induce autophagy. Strong antitumor effect was also observed on primary tumor cells while sparing normal hematopoiesis ex vivo. In a murine xenograft model established with subcutaneous injection of Namalwa cells, dual treatment efficiently blocked tumor growth, inhibited MYC and induced in situ autophagy.. These findings confirmed the synergistic effect of the HDAC and MTOR inhibitors on Burkitt leukemia/lymphoma, and provided an insight into clinical application of targeting autophagy in treating MYC-associated lymphoid malignancies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Burkitt Lymphoma; Cell Line, Tumor; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Mice; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Valproic Acid; Xenograft Model Antitumor Assays

Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Bone Marrow Cells; Cytogenetics; Cytokines; Female; Humans; Indazoles; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; RNA, Messenger; Signal Transduction; Sirolimus; Stromal Cells; Sulfonamides; TOR Serine-Threonine Kinases; Young Adult

To determine that 1) an age-dependent loss of inducible autophagy underlies the failure to recover from AKI in older, adult animals during endotoxemia, and 2) pharmacologic induction of autophagy, even after established endotoxemia, is of therapeutic utility in facilitating renal recovery in aged mice.. Murine model of endotoxemia and cecal ligation and puncture (CLP) induced acute kidney injury (AKI).. Academic research laboratory.. C57Bl/6 mice of 8 (young) and 45 (adult) weeks of age.. Lipopolysaccharide (1.5 mg/kg), Temsirolimus (5 mg/kg), AICAR (100 mg/kg).. Herein we report that diminished autophagy underlies the failure to recover renal function in older adult mice utilizing a murine model of LPS-induced AKI. The administration of the mTOR inhibitor temsirolimus, even after established endotoxemia, induced autophagy and protected against the development of AKI.. These novel results demonstrate a role for autophagy in the context of LPS-induced AKI and support further investigation into like interventions that have potential to alter the natural history of disease.

Topics: Acute Kidney Injury; Aminoimidazole Carboxamide; Animals; Autophagy; Class III Phosphatidylinositol 3-Kinases; Endotoxemia; Lipopolysaccharides; Male; Mice; Protein Kinase Inhibitors; Ribonucleotides; Sirolimus; TOR Serine-Threonine Kinases

The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI-779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic delivery of CCI-779 prevented the development of LID and significantly alleviated the severity of dyskinesia in L-DOPA-primed animals. This was associated with a reduced activation of the mTOR pathway in striatal medium spiny neurons. Drugs with mTOR inhibiting activity that are actively developed in cancer research may be of interest for the management of LID in PD patients.

Topics: Animals; Antiparkinson Agents; Dyskinesia, Drug-Induced; Female; Levodopa; Parkinson Disease; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Sorafenib is an orally administered active multikinase inhibitor for metastatic renal cell carcinoma that is now considered a standard agent. Skin toxicity, such as hand-foot skin reaction, is one of the frequent adverse effects of sorafenib. On the other hand, sorafenib-induced erythema multiforme is very rare, and Stevens-Johnson syndrome and toxic epidermal necrolysis induced by sorafenib have not been reported. We report the first case of Stevens-Johnson syndrome caused by sorafenib for metastatic renal cell carcinoma.

Topics: Aged; Betamethasone; Carcinoma, Renal Cell; Fatal Outcome; Humans; Kidney Neoplasms; Male; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prednisolone; Sirolimus; Skin; Sorafenib; Stevens-Johnson Syndrome

Experience with treatment of hemodialyzed patients by targeted therapy is limited to the few cases reported. Little information has been provided on the safety and toxicity profile of temsirolimus and sorafenib when administered in hemodialyed patients with renal cell carcinoma (RCC). Herein, we report an RCC patient undergoing hemodialysis treated with temsirolimus and sorafenib for 16 months. The patient was a 69-year-old man who was diagnosed with right RCC. He underwent nephrectomy for a pT1b tumor in December 2002. Hemodialysis was introduced in July 2003 (7 months after nephrectomy). Seven years later, CT showed retroperitoneal nodal metastases. He was started on temsirolimus. Although 8 cycles of this therapy were done, we discontinued it because of progressive disease. The CTCAE (Common Terminology Criteria for Adverse Events) grade 3 adverse events were thrombopenia, but no adverse events of grade 4 or greater developed. Secondly, he was started on sorafenib. CT showed a partial response with a 45% decrease in tumor bulk using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. He has partial response for 13 months. He presented high blood pressure requiring pharmacological treatment, but no adverse events of grade 4 or greater developed. Patients with terminal renal failure can be offered temsirolimus and sorafenib treatment with close clinical and laboratory monitoring. Treatment of RCC patient undergoing hemodialysis by targeted therapy appears to be feasible and effective.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Male; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Renal Dialysis; Sirolimus; Sorafenib

Targeted therapies directed at commonly overexpressed pathways in melanoma have clinical activity in numerous trials. Little is known about how these therapies influence microRNA (miRNA) expression, particularly with combination regimens. Knowledge of miRNAs altered with treatment may contribute to understanding mechanisms of therapeutic effects, as well as mechanisms of tumor escape from therapy. We analyzed miRNA expression in metastatic melanoma tissue samples treated with a novel combination regimen of Temsirolimus and Bevacizumab. Given the preliminary clinical activity observed with this combination regimen, we hypothesized that we would see significant changes in miRNA expression with combination treatment.. Using microarray analysis we analyzed miRNA expression levels in melanoma samples from a Cancer Therapy Evaluation Program-sponsored phase II trial of combination Temsirolimus and Bevacizumab in advanced melanoma, which elicited clinical benefit in a subset of patients. Pre-treatment and post-treatment miRNA levels were compared using paired t-tests between sample groups (patients), using a p-value < 0.01 for significance.. microRNA expression remained unchanged with Temsirolimus alone; however, expression of 15 microRNAs was significantly upregulated (1.4 to 2.5-fold) with combination treatment, compared to pre-treatment levels. Interestingly, twelve of these fifteen miRNAs possess tumor suppressor capabilities. We identified 15 putative oncogenes as potential targets of the 12 tumor suppressor miRNAs, based on published experimental evidence. For 15 of 25 miRNA-target mRNA pairings, changes in gene expression from pre-treatment to post-combination treatment samples were inversely correlated with changes in miRNA expression, supporting a functional effect of those miRNA changes. Clustering analyses based on selected miRNAs suggest preliminary signatures characteristic of clinical response to combination treatment and of tumor BRAF mutational status.. To our knowledge, this is the first study analyzing miRNA expression in pre-treatment and post-treatment human metastatic melanoma tissue samples. This preliminary investigation suggests miRNAs that may be involved in the mechanism of action of combination Temsirolimus and Bevacizumab in metastatic melanoma, possibly through inhibition of oncogenic pathways, and provides the preliminary basis for further functional studies of these miRNAs.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cell Line, Tumor; Cluster Analysis; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Melanoma; MicroRNAs; Molecular Targeted Therapy; Pilot Projects; Proto-Oncogene Proteins B-raf; Reproducibility of Results; Sirolimus

The objective of this study was to characterise the mechanism underlying acquired resistance to temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), in renal cell carcinoma (RCC).. A parental human RCC cell line, ACHN (ACHN/P), was continuously exposed to increasing doses of up to 20 μM of temsirolimus, and a cell line resistant to temsirolimus (ACHN/R), showing a sixfold higher IC50 than that of ACHN/P, was developed.. Following treatment with temsirolimus, phosphorylation of S6 kinase in ACHN/P was markedly inhibited, whereas there was no detectable expression of phosphorylated S6 in ACHN/R before and after temsirolimus treatment. However, AKT and p44/42 mitogen-activated protein kinase (MAPK) were constitutively phosphorylated even after temsirolimus treatment in ACHN/R, but not in ACHN/P. There was no significant difference between the sensitivities of ACHN/P and ACHN/R to KU0063794, a dual inhibitor of mTOR complex 1 (mTORC1) and mTORC2. Similar sensitivities to temsirolimus in ACHN/P and ACHN/R could be achieved by additional treatment with specific inhibitors of AKT- and MAPK-signaling pathways.. The activation of signal transduction pathways via mTORC2, but not via mTORC1, may have an important role in the acquisition of a resistant phenotype to temsirolimus in RCC.

Topics: Animals; Apoptosis; Butadienes; Carcinoma, Renal Cell; Cell Line, Tumor; Chromones; Drug Resistance, Neoplasm; Humans; Kidney Neoplasms; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases; Morpholines; Multiprotein Complexes; Nitriles; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The aim of this study was to illustrate the mechanism of inhibiting the cell growth in diffuse large B-cell lymphoma by histone deacetylase inhibitor valproic acid (VPA) combined with mTOR inhibitor temsirolimus (TEM). MTT assay and Wright's stain were used to assess cell growth inhibition and to detect the cell morphological changes respectively. The cell apoptosis, cell cycle and cell autophagy were determined by flow cytometry. Ultrastructure changes were confirmed by electron microscopy. Protein changes were detected by Western blot. The results showed that both VPA and TEM alone inhibited cell proliferation and the effect was more obvious in the combination group. VPA combined with TEM induced cell arrest in G0/G1 phase and upregulated the expression of autophagy-related protein LC3, without cell apoptosis. Moreover, typical autophagosomes were observed, further confirming the presence of autophagy. Western blot showed the changes of proteins involved in autophagy signaling pathway. VPA decreased HDAC1 and HDAC3 expression and increased histone acetylation, suggesting that VPA also affected lymphoma cell proliferation through epigenetic modification. It is concluded that the combined treatment of VPA and TEM induces cell cycle arrest and cell autophagy, which provides a new clue for their clinical application in diffuse large B-cell lymphoma.

Topics: Autophagy; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Epigenesis, Genetic; Histone Deacetylase 1; Histone Deacetylases; Humans; Lymphoma, Large B-Cell, Diffuse; Microtubule-Associated Proteins; Sirolimus; Valproic Acid

Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but data from randomized trials on the sequential use of temsirolimus are lacking. We retrospectively studied the efficacy and safety of temsirolimus therapy following failure of rTKI therapy.. Twenty-nine patients treated with temsirolimus (25 mg/week) following progression on rTKI therapy were studied at four institutions. All patients had failed at least one prior rTKI therapy (sunitinib, n = 6; sorafenib, n = 1; both, n = 22). Over 80% had two or more prior therapies. Data on efficacy (response assessment, progression-free survival [PFS], overall survival [OS]) and safety (NCI-CTC) were analyzed.. Adverse events occurred in 90% of patients with the majority being grade 1 (n = 4, 14%) or grade 2 (n = 12, 41%). Most grade 3/4 toxicities (n = 10, 34%) were manageable and included anemia (n = 4, 14%), leukopenia/neutropenia (n = 2, 7%), hyperglycemia (n = 1, 3%), acidosis/alkalosis (n = 2, 7%), and infection (n = 1, 3%). One patient discontinued temsirolimus for grade 3 pneumonitis. Median (range) PFS and OS were 5.1 months (1-10.4) and 18.0 months (12.6-23.3), respectively. Best response included partial response (n = 1) and stable disease (n = 15) for a disease control rate of 55%, and disease progression of 45% (n = 13).. Temsirolimus after rTKI failure appears to provide promising safety and efficacy comparable to other treatment options in pretreated patients with mRCC.

Topics: Adult; Aged; Carcinoma, Renal Cell; Disease Progression; Female; Follow-Up Studies; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Treatment Failure; Treatment Outcome

An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.

Topics: Adult; Aged; Animals; Astrocytoma; Cell Line, Tumor; Cell Movement; Female; Glioblastoma; Humans; Male; Mice; Mice, Inbred Strains; Middle Aged; Neoplasm Invasiveness; Protein Kinase Inhibitors; RGS Proteins; Sirolimus; TOR Serine-Threonine Kinases

Rapamycin is a macrocyclic lactone currently used for the treatment of cancer and for the prevention of transplant rejection. The primary pharmacological mode of action of rapamycin occurs through the inhibition (blocking) of the mammalian target of rapamycin (mTOR). By doing so, rapamycin interferes with the phosphoinositide 3-kinase (PI3K)-Akt-mTOR axis that controls several cellular functions involving cell growth, proliferation and angiogenesis. The frequent activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in advanced prostate cancer has provided a rationale for the use of mTOR inhibitors in this setting. We carried out a comparative study on the effects of rapamycin and temsirolimus on the in vitro and in vivo growth of the prostate cancer cell lines, LnCap and PC3. Our results demonstrate that rapamycin and temsirolimus exert similar in vitro and in vivo anti-proliferative effects against prostate cancer cells.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Humans; Male; Mice; Neoplasm Invasiveness; Prostatic Neoplasms; Sirolimus; Xenograft Model Antitumor Assays

Heat shock protein 90 (HSP90) and mammalian target of rapamycin (mTOR) are involved in the molecular pathogenesis of advanced oral squamous cell carcinoma. HSP90 inhibitors are capable of effectively interfering with multiple signaling pathways, including the mTOR signaling pathway. However, the combined effects of HSP90 and mTOR inhibitors on oral squamous cell carcinoma are still unknown. In this study, we investigated the dual treatment of the novel HSP90 inhibitor NVP-AUY922 and temsirolimus against oral squamous cell carcinoma.. The effect of the combination of NVP-AUY922 and temsirolimus on oral squamous cell carcinoma in vitro and in vivo was determined by MTS assay and mouse xenograft models. The effect of the combination on angiogenesis was determined by tube formation assay and angioreactor.. The combination treatment of NVP-AUY922 and temsirolimus significantly inhibited the proliferation of SAS oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. We have clearly shown that the combination treatment of NVP-AUY922 and temsirolimus inhibited vascular formation both in vitro and in vivo. Moreover, the combination treatment of NVP-AUY922 and temsirolimus prolonged the survival rate in mice xenografted with oral squamous cell carcinoma.. Here, we showed the activity of a combination of mTOR and HSP90 inhibitors for the treatment of advanced oral squamous carcinoma.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Line, Tumor; Cells, Cultured; Female; Head and Neck Neoplasms; HSP90 Heat-Shock Proteins; Human Umbilical Vein Endothelial Cells; Humans; Isoxazoles; Mice; Mice, Nude; Molecular Targeted Therapy; Mouth Neoplasms; Neoplasm Proteins; Neovascularization, Pathologic; Protein Kinase Inhibitors; Random Allocation; Resorcinols; Sirolimus; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The National Comprehensive Cancer Network (NCCN) guidelines suggest the use of inhibitors of mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus, as first- and second-line therapy, respectively, for advanced or metastatic renal cell carcinoma (mRCC). However, adherence to this recommendation in clinical practice and the use of these 2 agents in mRCC is unknown.. We determined the prescribing patterns of temsirolimus and everolimus in a retrospective longitudinal cohort study of patients with mRCC receiving clinical care within The US Oncology Network. Outpatient health care use in patients with mRCC was derived for the categories of laboratory visits, acute care visits, minor procedures, radiation therapy, drug/medication use, and other services.. Among 462 patients with mRCC, 144 (31%) were treated with everolimus and 318 (69%) were treated with temsirolimus. The use of temsirolimus vs. everolimus as first-, second-, and third-line therapy was 50.7% vs. 16.7%, 30.1% vs. 42.1%, and 19.3% vs. 83.2%, respectively. Despite similarities in disease stage and demographic features, compared with temsirolimus, everolimus use was independently associated with lower use of outpatient health care resources, regardless of the line of therapy.. Notwithstanding the potential limitation that this was an observational retrospective study, our results indicate that everolimus results in substantial savings in the use of resources relative to temsirolimus. In a large geographically dispersed network of community-based oncology practices, both of these agents are used frequently outside of NCCN guidelines. A direct comparison of the efficacy and costs of everolimus vs. temsirolimus for mRCC is warranted.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Guideline Adherence; Humans; Kidney Neoplasms; Longitudinal Studies; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

We retrospectively investigated the efficacy and safety of temsirolimus, an inhibitor of the mammalian target of rapamycin, in patients with metastatic renal cell carcinoma (mRCC) on hemodialysis (HD).. This study included ten HD patients who were diagnosed with mRCC following radical nephrectomy and subsequently treated with temsirolimus between December 2010 and June 2012. Medical records of these patients were reviewed to evaluate the response to temsirolimus and treatment-related toxicities.. Baseline characteristics of the patients are as follows: median age was 61 years, five patients had a Karnofsky performance status of ≤80, and two, six, and two patients were classified into favorable, intermediate, and poor risk group, respectively, according to the Memorial Sloan-Kettering Cancer Center risk model. Initially, all patients received 25 mg intravenous temsirolimus weekly; however, dose modification was necessary in four patients, resulting in a relative dose intensity of 89.5 % throughout this study. All patients, except for one with progressive disease, were judged to have stable disease following treatment with temsirolimus. Six patients are still under treatment with temsirolimus, whereas four have stopped receiving temsirolimus because of the occurrence of progressive disease in three and that of adverse events (AEs) in one. Although all patients experienced AEs related to temsirolimus, severe AEs corresponding to ≥ grade 3 occurred in only four, including thrombocytopenia in two, anemia in one, and asthenia in one.. Treatment with temsirolimus is well tolerated and could provide comparatively favorable cancer control in Japanese mRCC patients undergoing HD.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Renal Dialysis; Retrospective Studies; Sirolimus

Hantavirus pulmonary syndrome (HPS) is a severe respiratory disease characterized by pulmonary edema, with fatality rates of 35 to 45%. Disease occurs following infection with pathogenic New World hantaviruses, such as Andes virus (ANDV), which targets lung microvascular endothelial cells. During replication, the virus scavenges 5'-m(7)G caps from cellular mRNA to ensure efficient translation of viral proteins by the host cell cap-dependent translation machinery. In cells, the mammalian target of rapamycin (mTOR) regulates the activity of host cap-dependent translation by integrating amino acid, energy, and oxygen availability signals. Since there is no approved pharmacological treatment for HPS, we investigated whether inhibitors of the mTOR pathway could reduce hantavirus infection. Here, we demonstrate that treatment with the FDA-approved rapamycin analogue temsirolimus (CCI-779) blocks ANDV protein expression and virion release but not entry into primary human microvascular endothelial cells. This effect was specific to viral proteins, as temsirolimus treatment did not block host protein synthesis. We confirmed that temsirolimus targeted host mTOR complex 1 (mTORC1) and not a viral protein, as knockdown of mTORC1 and mTORC1 activators but not mTOR complex 2 components reduced ANDV replication. Additionally, primary fibroblasts from a patient with tuberous sclerosis exhibited increased mTORC1 activity and increased ANDV protein expression, which were blocked following temsirolimus treatment. Finally, we show that ANDV glycoprotein Gn colocalized with mTOR and lysosomes in infected cells. Together, these data demonstrate that mTORC1 signaling regulates ANDV replication and suggest that the hantavirus Gn protein may modulate mTOR and lysosomal signaling during infection, thus bypassing the cellular regulation of translation.

Topics: Antiviral Agents; Cells, Cultured; Gene Knockdown Techniques; Humans; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Orthohantavirus; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Virus Replication

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Male; Middle Aged; Randomized Controlled Trials as Topic; Sirolimus; Tuberculosis

A 63-year-old man presenting with a 7.2-cm right renal mass, an inferior vena cava tumor thrombus, and pulmonary metastases underwent renal mass biopsy that revealed clear cell renal cell carcinoma. Temsirolimus (25 mg weekly) was given because of the extent of the disease and poor performance status, which resulted in a marked reduction in the tumor thrombus (from level III to level I) after 20 weeks of treatment. Subsequently, radical nephrectomy and tumor thrombectomy were carried out. Final pathological analysis confirmed the diagnosis of high-grade clear cell carcinoma (pT4N0M1). One year after initiation of temsirolimus therapy, the patient remained alive despite the presence of disease.

Topics: Adenocarcinoma, Clear Cell; Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Sirolimus; Thrombosis; Vena Cava, Inferior

Limited information on real-world treatment patterns of targeted agents for metastatic renal cell carcinoma (mRCC) is available to inform their use in clinical practice.. This retrospective observational study used US claims data (from January 2007 to November 2010) to identify treatment patterns, including treatment duration and dosing, for molecular-targeted agents (sunitinib, sorafenib, pazopanib, bevacizumab, and temsirolimus) indicated in first-line management of advanced and/or mRCC. The study included adult patients with mRCC who were observable for ≥3 months after initiation of their first-line therapy with a targeted agent. Descriptive analyses were conducted for observed treatment patterns.. Of the 273 patients on first-line therapy identified and included in the sample, 235 patients were treated with sunitinib, 16 patients with sorafenib, and 15 patients with temsirolimus. Pazopanib and bevacizumab were excluded from the analysis due to the small sample size, n < 10. The median observed treatment durations were sunitinib 98 days, sorafenib 121 days, and temsirolimus 78 days. Approximately 76% (178/235) of patients who received sunitinib initiated therapy at the indicated dose of 50 mg; 65% of these patients were not observed filling a fourth prescription, whereas 23% maintained their starting dose and 12% experienced dose reduction at their 4+ fill. The mean starting dose for patients who initiated on sorafenib (n = 16) was 725 mg and for temsirolimus (n = 15) was 25 mg: their study samples were insufficient for further, meaningful dosing analyses.. Results of this study suggest that opportunities exist to improve treatment duration in clinical practice and to better understand influences on treatment and dose changes.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Cohort Studies; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; United States

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Enzyme Activation; Esophageal Neoplasms; Humans; Mice; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

The aim of this study was to elucidate whether the treatment of a prostate carcinoma cell line (LNCaP) and LNCaP-derived tumors with the histone deacetylase (HDAC) inhibitor valproate in combination with the mammalian target of rapamycin (mTOR) inhibitor temsirolimus resulted in synergistic effects on cell proliferation and tumor growth. LNCaP cells were treated with valproate, temsirolimus or a combination of both. The proliferation rates and the expression of key markers of tumorigenesis were evaluated. In in vivo experiments, LNCaP cells were implanted into immune-suppressed male nude mice. Mice were treated with valproate (per os), temsirolimus (intravenously) or with a combination of both. Tumor volumes were calculated and mRNA expression was quantified. The incubation of LNCaP cells with the combination of valproate and temsirolimus resulted in a decrease of cell proliferation with an additive effect of both drugs in comparison to the single treatment. In particular, the combined application of valproate and temsirolimus led to a significant upregulation of insulin-like growth factor-binding protein-3 (IGFBP-3), which mediates apoptosis and inhibits tumor cell proliferation. In the mouse model, we found no significant differences in tumor growth between the different treatment arms but immunohistological analyses showed that tumors treated with a combination of valproate and temsirolimus, but not with the single drugs alone, exhibited a significant lower proliferation capacity.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Male; Mice; Mice, Nude; Prostate; Prostatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Valproic Acid

To provide an updated review of adverse events associated with sunitinib, pazopanib, bevacizumab, temsirolimus, axitinib, everolimus and sorafenib and their management.. We performed a PubMed and Cochrane-based review of side effects associated with the seven agents including product monographs to provide an outline of treatment measures aiming to reduce their toxicities. Subject and outcome of interest, design type, sample size, pertinence and quality, and detail of reporting were the indicators of manuscript quality.. All targeted therapies cause adverse events. Most adverse events may be prevented or tested before they escalate to severe levels.. Prevention, early recognition, and prompt management of side effects are of key importance and avoid unnecessary dose reductions, which may undermine treatment efficacy.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Rapamycin analogs, temsirolimus and everolimus, are approved for the treatment of advance renal cell carcinoma (RCC). Currently approved agents inhibit mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). However, the mTOR kinase exists in two distinct multiprotein complexes, mTORC1 and mTORC2, and both complexes may be critical regulators of cell metabolism, growth and proliferation. Furthermore, it has been proposed that drug resistance develops due to compensatory activation of mTORC2 signaling during treatment with temsirolimus or everolimus. We evaluated Ku0063794, which is a small molecule that inhibits both mTOR complexes. Ku0063794 was compared to temsirolimus in preclinical models for renal cell carcinoma. Ku0063794 was effective in inhibiting the phosphorylation of signaling proteins downstream of both mTORC1 and mTORC2, including p70 S6K, 4E-BP1 and Akt. Ku0063794 was more effective than temsirolimus in decreasing the viability and growth of RCC cell lines, Caki-1 and 786-O, in vitro by inducing cell cycle arrest and autophagy, but not apoptosis. However, in a xenograft model there was no difference in the inhibition of tumor growth by Ku0063794 or temsirolimus. A potential explanation is that temsirolimus has additional effects on the tumor microenvironment. Consistent with this possibility, temsirolimus, but not Ku0063794, decreased tumor angiogenesis in vivo, and decreased the viability of HUVEC (Human Umbilical Vein Endothelial Cells) cells in vitro at pharmacologically relevant concentrations. Furthermore, expression levels of VEGF and PDGF were lower in Caki-1 and 786-O cells treated with temsirolimus than cells treated with Ku0063794.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Carcinoma, Renal Cell; Cell Cycle Proteins; Cell Proliferation; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Morpholines; Multiprotein Complexes; Neovascularization, Pathologic; Oncogene Protein v-akt; Phosphoproteins; Pyrimidines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous

pH-sensitive liposomes (HHG2C(18)-L and PEGHG2C(18)-L) based on zwitterionic oligopeptide lipids as anticancer drug carriers were developed and evaluated for effective intracellular delivery and enhanced antitumor activity. The amino acid-based lipids, 1,5-dioctadecyl-l-glutamyl 2-histidyl-hexahydrobenzoic acid (HHG2C(18)) and 1,5-distearyl N-(N-α-(4-mPEG2000) butanedione)-histidyl-l-glutamate (PEGHG2C(18)), were synthesized, which have the multistage pH-response to tumor microenvironmental pH (pH(e), pH 6.0-7.0) and endosomal/lysosomal pH (pH(i), pH 4.0-6.0) successively. HHG2C(18)-L contains HHG2C(18), while PEGHG2C(18)-L includes HHG2C(18) and PEGHG2C(18). Both of them displayed the capability of charge conversion to the surrounding pH. The zeta potentials of HHG2C(18)-L and PEGHG2C(18)-L were negative at pH 7.4, whereas positive at pH 6.5 and more positive at lower pH. Coumarin 6-loaded HHG2C(18)-L (C6/HHG2C(18)-L) and PEGHG2C(18)-L (C6/PEGHG2C(18)-L) showed higher tumor cellular uptake due to electrostatic absorptive endocytosis at pH(e) (pH 6.5), produced proton sponge effect for endo-lysosomal escape, and accumulated to the mitochondria based on stronger positive charge by the hydrolysis of a pH-sensitive linker at pH(i) (pH 5.5 and pH 4.5). Furthermore, temsirolimus (CCI-779)-loaded HHG2C(18)-L (CCI-779/HHG2C(18)-L) and PEGHG2C(18)-L (CCI-779/PEGHG2C(18)-L) had significantly higher antiproliferative and apoptosis inducing effects toward the human renal carcinoma (A498) cells at pH 6.5 relative to that at pH 7.4. The half maximal inhibitory concentration (IC50) of CCI-779/HHG2C(18)-L and CCI-779/PEGHG2C(18)-L were about 3 μg/mL and 5 μg/mL at pH 6.5, 1.67-fold and 1.60-fold improved relative to that at pH 7.4, respectively. The total apoptotic ratio of CCI-779/HHG2C(18)-L and CCI-779/PEGHG2C(18)-L increased from 9.90% and 7.78% at pH 7.4 to 19.53% and 12.10% at pH 6.5, respectively. In vivo, CCI-779/PEGHG2C(18)-L after intravenous administration presented remarkably higher bioavailability and blood persistence compared with unPEGylated CCI-779/HHG2C(18)-L, and had the strongest antitumor efficacy against xenograft renal cancer (Renca) tumor models. Accordingly, the results provide the feasibility of using pH-sensitive zwitterionic oligopeptide lipids to extend the applications of liposomes to efficient anticancer drug delivery in cancer therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Delivery Systems; Endocytosis; Humans; Hydrogen-Ion Concentration; Lipids; Liposomes; Male; Mice; Mitochondria; Oligopeptides; Rats; Rats, Sprague-Dawley; Sirolimus; Tumor Microenvironment

The potential therapeutic benefits of cannabinoid compounds have raised interest in understanding the molecular mechanisms that underlie cannabinoid-mediated effects. We previously showed that the acute amnesic-like effects of delta9-tetrahydrocannabinol (THC) were prevented by the subchronic inhibition of the mammalian target of rapamycin (mTOR) pathway. In the present study, we assess the relevance of the mTOR pathway in other acute and chronic pharmacological effects of THC. The rapamycin derivative temsirolimus, an inhibitor of the mTOR pathway approved by the Food and Drug Administration, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC. In contrast, THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception are not sensitive to the mTOR inhibition. In addition, a clear tolerance to THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception was observed after chronic treatment, but not to its anxiogenic- and amnesic-like effects. Temsirolimus pre-treatment prevented the amnesic-like effects of chronic THC without affecting the downregulation of CB1 receptors (CB1R) induced by this chronic treatment. Instead, temsirolimus blockade after chronic THC cessation did not prevent the residual cognitive deficit produced by chronic THC. Using conditional knockout mice lacking CB1R in GABAergic or glutamatergic neurons, we found that GABAergic CB1Rs are mainly downregulated under chronic THC treatment conditions, and CB1-GABA-KO mice did not develop cognitive deficits after chronic THC exposure. Therefore, mTOR inhibition by temsirolimus allows the segregation of the potentially beneficial effects of cannabinoid agonists, such as the anxiolytic and antinociceptive effects, from the negative effects, such as anxiogenic- and amnesic-like responses. Altogether, these results provide new insights for targeting the endocannabinoid system in order to prevent possible side effects.

Topics: Amnesia; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Brain; Down-Regulation; Dronabinol; Drug Interactions; Drug Tolerance; Hypothermia; Locomotion; Male; Mice; Mice, Knockout; Nociception; Receptor, Cannabinoid, CB1; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway promotes melanoma tumor growth and survival while suppressing autophagy, a catabolic process through which cells collect and recycle cellular components to sustain energy homeostasis in starvation. Conversely, inhibitors of the PI3K/AKT/mTOR pathway, in particular the mTOR inhibitor temsirolimus (CCI-779), induce autophagy, which can promote tumor survival and thus, these agents potentially limit their own efficacy. We hypothesized that inhibition of autophagy in combination with mTOR inhibition would block this tumor survival mechanism and hence improve the cytotoxicity of mTOR inhibitors in melanoma. Here we found that melanoma cell lines of multiple genotypes exhibit high basal levels of autophagy. Knockdown of expression of the essential autophagy gene product ATG7 resulted in cell death, indicating that survival of melanoma cells is autophagy-dependent. We also found that the lysosomotropic agent and autophagy inhibitor hydroxychloroquine (HCQ) synergizes with CCI-779 and led to melanoma cell death via apoptosis. Combination treatment with CCI-779 and HCQ suppressed melanoma growth and induced cell death both in 3-dimensional (3D) spheroid cultures and in tumor xenografts. These data suggest that coordinate inhibition of the mTOR and autophagy pathways promotes apoptosis and could be a new therapeutic paradigm for the treatment of melanoma.

Topics: Allosteric Regulation; Animals; Autophagy; Autophagy-Related Protein 7; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Drug Synergism; Gene Knockdown Techniques; Humans; Hydroxychloroquine; Male; Melanoma; Mice; Mice, Nude; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitin-Activating Enzymes

pH homeostasis is essential for development, proliferation and apoptosis of cells. Once the pH balances are broken, cell functions and survival will be affected. Nevertheless, moderate acidosis could result in adaptive responses for cell survival and increase tolerance to harmful stress. Here we found that acidic preconditioning (APC) could significantly increase the survival rate of Daphnia pulex, a freshwater invertebrate, during severe hypoxic insult. Meanwhile, the acidic treatment significantly increased the gene expression of hypoxia inducible factor (HIF). Both echinomycin, an inhibitor of HIF, and compound C, an inhibitor of AMP-activated protein kinase (AMPK), could effectively eliminate the acid-induced hypoxic tolerance and the enhanced transcription of HIF. Temsirolimus, an inhibitor of mammalian Target of Rapamycin (mTOR), though effectively abolished the increased transcription of HIF, improved the APC-mediated protection. This result suggests that the involvement of the HIF and AMPK and mTOR could signal the pathways in APC-induced protection against hypoxic insult.

Topics: Acids; Adaptation, Physiological; AMP-Activated Protein Kinases; Animals; Daphnia; Hypoxia; Hypoxia-Inducible Factor 1; Ischemic Preconditioning; Pyrazoles; Pyrimidines; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases

mTOR inhibitor rapamycin and its analogs are lipophilic, demonstrate blood-brain barrier penetration, and have shown promising antitumor effects in several types of refractory tumors. We thus try to explore the therapeutic effects of mTOR inhibitors on brain metastasis models. We examined the effects of different dose of mTOR inhibitors (rapamycin, Temsirolimus-CCI-779) on cell invasion in two brain metastatic breast cancer cell lines (MDA-MB231-BR and CN34-BrM2). Antibody microarray and immunoblotting were applied to detect signaling pathways underlying the dose differential drug effects. The in vivo effects of single drug (CCI-779), and drug combination of CCI-779 with SL327 (a brain penetrant MEK inhibitor) to eliminate the unfavorable activation of MAPK pathway were evaluated in MDA-MB231-BR brain metastases xenograft mice. The two mTOR inhibitors, rapamycin and CCI-779, inhibited the invasion of brain metastatic cells only at a moderate concentration level, which was lost at higher concentrations secondary to activation of the MAPK signaling pathway. Pharmacological inhibition of ERK1/2 by PD98059 and SL327 restored the anti-invasion effects of mTOR inhibition in vitro. In vivo, a significant decrease was noted in the average number of micro and large metastatic lesions as well as the whole brain GFP expression in the CCI-779 1 mg/kg/day treated group compared with that in the vehicle group (P < 0.05). However, 10 mg/kg CCI-779 treatment did not show significant anti-metastasis effect on the animal model. High-dose CCI-779 eliciting the ERK MAPK activation in the brain metastatic lesion was corroborated. Combined with the brain penetrant MEK inhibitor SL327, high-dose CCI-779 significantly reduces the brain metastasis, and the combination treatment prohibited perivascular invasion of tumor cells and inhibits tumor angiogenesis in vivo. This study provides evidence on the potential value of CCI-779 as well as CCI-779 + SL327 in prohibiting breast cancer brain metastasis.

Topics: Aminoacetonitrile; Animals; Antineoplastic Agents; Brain Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Female; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Neoplasm Invasiveness; Neovascularization, Pathologic; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Renal cell carcinoma (RCC) with sarcomatoid features has an aggressive course. There is no standard treatment for this histological subtype. Some authors have previously reported the use of chemotherapy, but the activity of new agents against renal carcinoma with sarcomatoid differentiation has to be formally evaluated. Temsirolimus, an inhibitor of the mammalian target or rapamycin, is active in RCC, including those tumors with non-clear histologies. We have tested the activity of this agent in three consecutive patients. A first patient showed a rapid progression, dying 2 months after the diagnosis. The second patient showed clinical improvement and a partial response to lung metastasis that was maintained for 14 months. The third patient is still alive, evaluated as stable disease after 7 months on temsirolimus. Importantly, toxicity was not a main issue during the use of temsirolimus and only grade 2 hyperglycemia, asthenia, hyperlipidemia, and pleural effusion were detected. Temsirolimus is a valid therapy in this subset of patients, with some lasting stabilizations and with manageable toxicity.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Male; Middle Aged; Positron-Emission Tomography; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

First line treatment with temsirolimus is considered standard of care in poor risk patients with metastatic renal cell carcinoma. The role of temsirolimus in pretreated patients with any risk profile is unclear. The aim of this retrospective analysis was to investigate the impact of temsirolimus in patients who had progressed on various treatment lines.. From April 2007 to July 2009, all patients who had progressed on receptor-tyrosine kinase-inhibitors, VEGF-antibodies and other agents were treated with temsirolimus (25 mg weekly). Physical examination, white blood cell count and chemistry were obtained weekly and tumor response was assessed every 12 weeks.. Thirty patients with a median age of 68 years range (44-81) received treatment with temsirolimus. Most patients were categorized intermediate risk (60%) and the majority had three or more metastatic sites (56.7%). Temsirolimus was median the fourth (range 2-5) systemic treatment line. Grade 3 and 4 toxicities were rare and consisted of anemia, thrombocytopenia and hyperglycemia. Objective remission and stable disease were achieved in 13.3% and 60% of the patients, respectively. The median progression free survival was 4.9 months (2.93-6.81 95% CI).. Temsirolimus appears feasible, safe and active in heavily pretreated patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Dose-Response Relationship, Drug; Feasibility Studies; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Retrospective Studies; Risk Assessment; Sirolimus; Treatment Outcome

Ionizing radiation (IR) is used frequently in the management of multiple tumor types, including both organ-confined and locally advanced prostate cancer (PCa). Enhancing tumor radiosensitivity could both reduce the amount of radiation required for definitive treatment and improve clinical outcome. Androgen suppression therapy improves clinical outcomes when combined with radiation therapy but is associated with significant acute and chronic toxicities; hence, there is a clear need for alternative means to increase the therapeutic window of radiotherapy. Herein, it is demonstrated that the mammalian target of rapamycin (mTOR) inhibitors rapamycin (sirolimus) and temsirolimus limit both hormone therapy (HT)-sensitive and castration-resistant PCa (CRPC) cell proliferation as single agents and have a profound radiosensitization effect when used in combination with IR. Importantly, the observed radiosensitization was influenced by the treatment schedule, in which adjuvant administration of mTOR inhibitors was most effective in limiting PCa cell population doubling. This schedule-dependent influence on in vitro treatment outcome was determined to be the result of relative effects on the cell cycle kinetics. Finally, adjuvant administration of either mTOR inhibitor tested after IR significantly decreased clonogenic cell survival of both HT-sensitive and CRPC cells compared with IR alone. Taken together, these data demonstrate that inhibition of mTOR confers a radiosensitization phenotype that is dependent on relative cell cycle kinetics and provide a foundation for clinical assessment.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Survival; Humans; Male; Prostatic Neoplasms; Radiation-Sensitizing Agents; Receptors, Androgen; Sirolimus; TOR Serine-Threonine Kinases; X-Rays

A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria.. Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers.. One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors.. Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Logistic Models; Male; Middle Aged; Multivariate Analysis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Risk Factors; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

The use of targeted therapies is increasing in the treatment of cancer. Monoclonal antibodies and tyrosine kinase inhibitors are the most commonly used but other classes such as mTOR inhibitors are increasingly prescribed. These treatments are often given in the long term in metastatic and maintenance treatments. It is therefore important to monitor the occurrence of immediate toxicities but also later and cumulative toxicities. Renal toxicities of targeted therapies are most often due to structural damages of the nephron. The anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor receptor (VEGFR) have renal side effects since growth factor receptors are expressed in the kidney. The toxicity of molecules such as bortezomib, erlotinib and lapatinib are less known. The approvals by the Food and Drugs Administration (FDA) and European Medicines Agency (EMA) of sorafenib, sunitinib and temsirolimus were based on studies of less than 3,000 patients. In this context, there is little data on their acute and chronic tolerance, including on the kidneys. This short review synthesizes the physiopathological hypotheses, early diagnosis and treatment of renal toxicity of major targeted therapies available in 2011.

Topics: Antibodies, Monoclonal; Benzenesulfonates; Boronic Acids; Bortezomib; Erlotinib Hydrochloride; Glomerulonephritis; Humans; Indoles; Kidney; Kidney Tubules; Lapatinib; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrazines; Pyridines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that belongs to the phosphatidylinositol kinase-related kinase family. We describe our molecular characterization of mTOR and its function (GenBank accession HM114224) in Cashmere goat (Capra hircus). The goat mTOR complementary DNA is 8617 bp, comprising an open reading frame of 7650 bp--corresponding to a polypeptide of 2549 amino acids--and a 909 bp 3' untranslated region with a polyA tract and a polyadenylation signal at nucleotides 8575-8580. In a bioinformatics analysis, goat mTOR has typical sites of activity and domains. mTOR mRNA was measured in brain, heart, testis, liver, spleen, kidney, and lung by real-time polymerase chain reaction, and the expression of mTOR in fetal fibroblasts was detected by western blot. The viability of fetal fibroblasts was inhibited on treatment with CCI-779, a specific inhibitor of mTOR. Our data supplied evidence that the transcription of mTOR was detected in the seven tissues in Cashmere goat, and mTOR protein was translated in fetal fibroblasts. The proliferation of fetal fibroblasts decreases on inhibition of mTOR.

Topics: Amino Acid Sequence; Animals; Blotting, Western; Cell Proliferation; Cells, Cultured; Cloning, Molecular; Fetus; Fibroblasts; Goats; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Kinase Inhibitors; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sequence Homology, Amino Acid; Sirolimus; Tissue Distribution; TOR Serine-Threonine Kinases

For rare diseases, standard treatments are often not available and essential study parameters are difficult or impossible to obtain. Therefore, designs of clinical trials for these diseases are often based on little information. Adaptive designs allow such trials to be started and to gain information during the study. Motivated by a trial for a rare subtype of renal-cell carcinoma, we present a two-stage adaptive design for right-censored time-to-event data and a two-sided test. After the first stage, one can stop for futility or continue with reestimated sample size. The properties of such designs are analyzed by simulation studies.

Topics: Algorithms; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Computer Simulation; Data Interpretation, Statistical; Humans; Indoles; Kidney Neoplasms; Proportional Hazards Models; Pyrroles; Rare Diseases; Research Design; Sample Size; Sirolimus; Sunitinib; Survival

Though uncommon, the collecting duct carcinoma (CDC) of Bellini is a very aggressive primary renal tumour occurring in less than 1% of all renal cell carcinoma (RCC) cases. This rare subtype was always excluded from the prospective trials with targeted therapies. Few data so far available concern the subgroup analyses from the expanded access programs with sorafenib and sunitinib, and from temsirolimus randomized study.. From December 2004 to May 2010, 333 patients with advanced RCC have been treated in our Institution with targeted therapies: of these, 7 (2.6%) were affected by CDC. General characteristics, symptoms, pathological features, treatments and patients' outcome were recorded.. All patients affected by CDC received targeted agents as first-line therapy: more precisely, 4 patients were treated with sorafenib, 2 with temsirolimus and 1 with sunitinib. After progression 2 patients received a second-line treatment with sunitinib. No patients were alive at 5 years. Five patients developed early progression of disease with a very short 4-month survival, while 2 cases had a long-lasting disease control with an overall survival time accounting for 49 and 19 months, respectively. Treatment-related adverse events were manageable consisting of fatigue, diarrhoea, hand-foot syndrome, hypertension and anemia, the latter being the most frequent. No treatment discontinuations due to adverse event were needed.. This investigation shows that targeted agents are safe, displaying some degree of activity in CDCs: therefore, they could be considered as an alternative in patients not eligible to chemotherapy regimens. Further studies including biomarkers as predictive factors of tumour biology and clinical features are required to improve the management of this challenging disease.

Topics: Adult; Aged; Benzenesulfonates; Carcinoma, Renal Cell; Female; Hand-Foot Syndrome; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib

The mammalian target of rapamycin (mTOR) and the microtubules are prominent druggable targets for hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we hypothesized that co-targeting of mTOR (by mTOR inhibitor temsirolimus) and the microtubule (by microtubule-destabilizing agent vinblastine) would be more efficacious than single targeting in HCC models. In vitro studies showed that effective inhibition of mTOR signaling with temsirolimus alone was able to suppress HCC cell growth in a dose-dependent manner. Among five cell lines tested, Huh7 was the most temsirolimus-sensitive (IC(50)=1.27±0.06μM), while Hep3B was the most temsirolimus-resistant (IC(50)=52.95±17.14μM). We found that co-targeting of mTOR (by temsirolimus) and the microtubule (by vinblastine, at low nM) resulted in marked growth inhibition in Huh7 cells and synergistic growth inhibition in Hep3B cells (achieving maximal growth inhibition of 80-90%), demonstrating potent antitumor activity of this novel combination. In vivo studies showed that temsirolimus treatment alone for 1 week was able to inhibit the growth of Huh7 xenografts. Strikingly, the temsirolimus/vinblastine combination induced a significant and sustained antitumor activity (up to 27 days post-treatment), with effective reduction of tumor vessel density in both Huh7 and Hep3B xenograft models. Mechanistic investigation revealed that this marked antitumor effect was accompanied by specific and concerted down-regulation of several key anti-apoptotic/survival proteins (survivin, Bcl-2, and Mcl-1), which was not observed in single agent treatments. Our findings demonstrated that the potent anti-cancer activity of this co-targeting strategy was indeed mediated in parts by inhibition of these key survival/anti-apoptotic proteins.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis Regulatory Proteins; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Inhibitor of Apoptosis Proteins; Liver Neoplasms; Male; Mice; Mice, Nude; Microtubules; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sirolimus; Survivin; TOR Serine-Threonine Kinases; Vinblastine; Xenograft Model Antitumor Assays

The mammalian target of rapamycin (mTOR) is a Ser/Thr kinase. It plays an evolutionarily conserved role in regulating cell growth, proliferation, survival, and metabolism via different cellular processes. The purpose of this study was to explore the inhibitory effects of CCI-779 (temsirolimus), a specific mTOR inhibitor, on mTOR signaling, and examine the mechanism of cell growth suppression by CCI-779 in Cashmere goat fetal fibroblasts (GFb cells). GFb cells were sensitive to CCI-779 and the survival rate of cells treated with >3.0 μM of CCI-779 was significantly reduced compared with the control (p<0.01). CCI-779 inhibited the phosphorylation of mTOR (at Ser2448) and S6 (at Ser240/244), and the expression of mTOR, p70S6K, and S6. Thus, CCI-779 was toxic to GFb cells, and it induced a dose-dependent decrease in cell proliferation and caused G1/S cell cycle arrest. Taken together, these data show that CCI-779 can inhibit mTOR signaling and proliferation in GFb cells in vitro. Therefore, mTOR is an important regulator for GFb cell growth and proliferation.

Topics: Animals; Cell Cycle Checkpoints; Enzyme Activation; Fetus; Fibroblasts; G1 Phase Cell Cycle Checkpoints; Goats; Protein Kinase Inhibitors; Ribosomal Protein S6 Kinases, 70-kDa; S Phase Cell Cycle Checkpoints; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Multitargeted tyrosine kinase inhibitors (TKIs) (such as Sunitinib and Sorafenib) and mTOR inhibitors (such as Temsirolimus) are effective in treating metastatic clear-cell renal cell carcinoma (CCRCC), by acting on different pathways in both tumour and endothelial cells. A study of their combined effect could be of major interest.. We studied endothelial and CCRCC cell lines treated with Sunitinib, Sorafenib, Temsirolimus and 2 drug combinations: Sunitinib-Temsirolimus and Sorafenib-Temsirolimus. We studied inhibition of proliferation with an MTT assay under normoxia and hypoxia, VEGF expression by quantitative RT-PCR and ELISA, and angiogenesis with a Matrigel assay.. TKIs and Temsirolimus inhibited proliferation of endothelial and tumour cell lines and inhibited angiogenesis. Anti-proliferative effects were more significant on cell lines with VHL gene inactivation and under hypoxic conditions. VEGF expression was induced by TKIs, but inhibited by Temsirolimus. The Sunitinib/Temsirolimus combination had synergistic or additive effects on the proliferation of tumour and endothelial cell lines. The Sorafenib-Temsirolimus combination had additive effects on the proliferation of most tumour cell lines, but not endothelial cell lines. Both combinations had additive effects on the inhibition of angiogenesis.. In our model, Sunitinib, Sorafenib and Temsirolimus had anti-tumour and anti-angiogenic effects. The combinations of Sunitinib or Sorafenib with Temsirolimus had additive or synergistic effects on the inhibition of tumour and endothelial cell proliferation, and on the inhibition of angiogenesis. This work could lead to new trials with lower-dose combinations to prevent side effects and enhance efficacy.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Drug Therapy, Combination; Human Umbilical Vein Endothelial Cells; Humans; Indoles; Kidney Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Cell Cycle Proteins; Drug Resistance, Neoplasm; Everolimus; Humans; Neoplasms; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Sirolimus; Tacrolimus Binding Protein 1A; TOR Serine-Threonine Kinases

Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Antineoplastic Agents; Autophagy; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Synergism; Enzyme Activation; Humans; Lymphoma, B-Cell; Lymphoma, T-Cell; Metformin; Mice; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Patients with adrenocortical carcinoma (ACC) need new treatment options. The aim of this study was to evaluate the effects of the mTOR inhibitors sirolimus and temsirolimus on human ACC cell growth and cortisol production. In H295, HAC15, and SW13 cells, we have evaluated mTOR, IGF2, and IGF1 receptor expressions; the effects of sirolimus and temsirolimus on cell growth; and the effects of sirolimus on apoptosis, cell cycle, and cortisol production. Moreover, the effects of sirolimus on basal and IGF2-stimulated H295 cell colony growth and on basal and IGF1-stimulated phospho-AKT, phospho-S6K1, and phospho-ERK in H295 and SW13 were studied. Finally, we have evaluated the effects of combination treatment of sirolimus with an IGF2-neutralizing antibody. We have found that H295 and HAC15 expressed IGF2 at a >1800-fold higher level than SW13. mTOR inhibitors suppressed cell growth in a dose-/time-dependent manner in all cell lines. SW13 were the most sensitive to these effects. Sirolimus inhibited H295 colony surviving fraction and size. These effects were not antagonized by IGF2, suggesting the involvement of other autocrine regulators of mTOR pathways. In H295, sirolimus activated escape pathways. The blocking of endogenously produced IGF2 increased the antiproliferative effects of sirolimus on H295. Cortisol production by H295 and HAC15 was inhibited by sirolimus. The current study demonstrates that mTOR inhibitors inhibit the proliferation and cortisol production in ACC cells. Different ACC cells have different sensitivity to the mTOR inhibitors. mTOR could be a target for the treatment of human ACCs, but variable responses might be expected. In selected cases of ACC, the combined targeting of mTOR and IGF2 could have greater effects than mTOR inhibitors alone.

Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Hydrocortisone; Insulin-Like Growth Factor II; Protein Kinase Inhibitors; Receptor, IGF Type 1; Sirolimus; TOR Serine-Threonine Kinases

Dermatologic adverse events stemming from anticancer therapies have become an increasingly frequent clinical problem. Inhibitors of mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus, have been associated with a high rate of skin eruptions, but their clinical and histopathologic characteristics have not been explored.. A retrospective analysis of patients who were referred to the Dermatology Service for diagnosis and management of rash in the setting of therapy with the mTOR inhibitors everolimus and temsirolimus was performed. The parameters that were studied included the time to onset, clinical presentation at the time of dermatologic evaluation, associated symptoms, evolution, results of microbiologic studies, concomitant medications, the need for dose reduction and/or treatment interruption because of rash, and routine histopathology.. In total, 13 patients were analyzed. Most rashes were mild (grade 1; 31%) and moderate (grade 2; 54%) in severity, and grade 3 rashes were observed only in 2 patients (15%). The trunk was the most frequently affected region (77%), with the scalp (23%), face (38%), neck (54%), and extremities (69%) also commonly involved. Erythematous papules and pustules constituted the predominant primary lesion morphology (62%). No unique or uniform histopathologic reaction pattern was observed. The most common reaction pattern was that of a mixed, spongiotic interface and perivascular dermatitis, which was observed in 7 of 11 patients (63%).. Although mTOR inhibitors may commonly induce erythematous papules and pustules, they are associated with a spectrum of lesion morphologies and a variety of histopathologic findings. Further clinicohistologic correlation studies are needed.

Topics: Adult; Aged; Antineoplastic Agents; Everolimus; Exanthema; Female; Humans; Male; Middle Aged; Sirolimus; TOR Serine-Threonine Kinases

Sequential therapy is a standard strategy used to overcome the limitations of targeted agents in metastatic renal cell carcinoma. It remains unclear whether a mammalian target of rapamycin (mTOR) inhibitor is a more effective second-line therapy after first-line vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) has failed than the alternative, VEGF TKI. A clinical database was used to identify all patients with renal cell carcinoma who failed at first-line VEGF TKI and then treated with second-line VEGF TKI or mTOR inhibitors in the Asan Medical Center. Patient medical characteristics, radiological response and survival status were assessed. Of the 83 patients who met the inclusion criteria, 41 received second-line VEGF TKI [sunitinib (n = 16) and sorafenib (n = 25)] and 42 were treated with mTOR inhibitors [temsirolimus (n = 11) and everolimus (n = 31)]. After a median follow-up duration of 23.9 months (95 % CI, 17.8-30.0), progression-free survival was 3.0 months for both groups [hazard ratio (HR, VEGF TKI vs. mTOR inhibitor) = 0.97, 95 % CI 0.59-1.62, P = 0.92]. Overall survival was 10.6 months for the VEGF TKI group and 8.2 months for the mTOR inhibitor group (HR = 0.98, 95 % CI 0.57-1.68, P = 0.94). The two groups did not differ significantly in terms of disease control rate (51 % for VEGF TKI and 59 % for mTOR inhibitor, P = 0.75). Second-line VEGF TKI seems to be as effective as mTOR inhibitors and may be a viable option as a second-line agent after first-line anti-VEGF agents have failed.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Enzyme Inhibitors; ErbB Receptors; Everolimus; Female; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Protein-Tyrosine Kinases; Pyrroles; Salvage Therapy; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome

Temsirolimus is an effective treatment for renal cell carcinoma. It is associated with increases in serum cholesterol, triglyceride, and glucose. We investigated whether changes of these biomarkers could predict its efficacy.. We examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to IFN or temsirolimus in the Global Advanced Renal Cell Carcinoma Trial. Using time-dependent proportional hazards models, we quantified the association between changes in these biomarkers from baseline with overall survival (OS) and progression-free survival (PFS). We also assess the extent to which changes of these biomarkers predict the effects of temsirolimus on survival.. Temsirolimus was associated with larger mean increases in cholesterol (1.02 mmol/L; P < 0.0001), triglycerides (0.32 mmol/L; P = 0.0008), and glucose (1.28 mmol/L; P < 0.0001) compared with IFN and improved survival rate (OS: HR = 0.76, P = 0.02; PFS: HR = 0.70, P = 0.001). Cholesterol increase during study was associated with longer survival (OS: HR = 0.77 per mmol/L, P < 0.0001; PFS: HR = 0.81 per mmol/L; P < 0.0001). Temsirolimus effect on cholesterol predicted its effect on survival with no additional survival advantage observed after adjusting for cholesterol change during study (OS: HR = 1.14, P = 0.37; PFS: HR = 0.88, P = 0.35). Temsirolimus effect on triglycerides or glucose did not predict its effect on survival, with survival advantage in favor of temsirolimus still observed after adjusting for these factors (P = 0.003 and P = 0.002).. Cholesterol increase is a potential predictor for temsirolimus efficacy. Longer survival in patients treated with temsirolimus was observed in those with larger increases in cholesterol. Prospectively designed biomarker studies of temsirolimus or other mTOR inhibitors are recommended.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Blood Glucose; Carcinoma, Renal Cell; Cholesterol; Disease-Free Survival; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Prognosis; Sirolimus; Triglycerides

Mammalian target of rapamycin (mTOR) inhibitors are approved for use in patients with metastatic renal cell carcinoma (mRCC) and are under investigation in several other malignancies. We assessed the incidence, clinical presentation and computed tomography (CT) findings of pneumonitis associated with mTOR inhibitors in mRCC. Correlation between radiological findings of pneumonitis and clinical outcome was also determined.. We retrospectively reviewed the clinical data and serial CT scans from patients with mRCC treated with either temsirolimus or everolimus. Serial chest CT scans were reviewed in consensus, read by two independent radiologists for the presence of pneumonitis, and corresponding clinical data were reviewed for symptoms and clinical outcome. The baseline and follow up CTs were reviewed to assess outcome to therapy.. The study population consisted of 46 pts, 21 treated with temsirolimus and 25 with everolimus (M:F 2.5:1; median 63 years, range 31-79 years). CT evidence of pneumonitis was seen in 14/46 pts (30%), at a median of 56days on mTOR inhibitor treatment (range 31-214 days). Respiratory symptoms at the time of radiographically detected pneumonitis, were observed in 7pts. Stable disease (SD) by Response Evaluation Criteria in Solid Tumours (RECIST) was achieved in 12/14 pts (86%) who developed radiographic pneumonitis compared to 14/32 (44%) without pneumonitis (p=0.01) The mean change of tumour long axis size for target lesions by RECIST, normalised for 30 days on therapy was -2.9% in the pneumonitis group and +4.3% in the non-pneumonitis group (p=.002).. Preliminary data suggest that pneumonitis may be a marker of stable disease by RECIST and therefore, of therapeutic benefit. Careful patient assessment should be undertaken before the drug is discontinued.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Pneumonia; Retrospective Studies; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome

Lee and colleagues report that increase in serum cholesterol is associated with improved clinical outcomes in patients with renal cell carcinoma treated with temsirolimus. Although these findings must be validated prospectively, it should also be determined if this marker is a true mechanism-based toxicity or an epiphenomenon associated with therapy.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cholesterol; Female; Humans; Kidney Neoplasms; Male; Sirolimus

Head and neck squamous cell carcinoma (HNSCC) is a group of tumors known to be sensitive to chemotherapy and radiotherapy in patients who are treatment naive. However, when recurrences do occur, these tumors generally become resistant and objective responses to therapy at that point tend to be less effective. There has been an increasing interest in developing novel molecular-targeted agents that specifically modulate growth factor and signaling pathways that are unregulated in HNSCC tumor cells. Combinations of vascular endothelial growth factor and mammalian target of rapamycin inhibitors have been used in some types of neoplasms, but no such efforts have been made in HNSCC. In this study, we investigated the in vitro, in vivo, and clinical effects of the temsirolimus (mammalian target of rapamycin inhibitor, Tem) and bevacizumab (antivascular endothelial growth factor antibody, Bev) combination. In-vitro studies were carried out on the A431 human squamous epidermoid carcinoma cell line and in-vivo studies were carried out on A431 tumor cells implanted on female Nu/Nu*nuBR (athymic nude) mice. Also, the effectiveness of the Tem and Bev combination was tested clinically in two separate clinical cases of chemoresistant HNSCC. The in-vitro, in-vivo, and clinical results showed that this combination can be significantly effective. In conclusion, we discuss the theoretical basis of the molecular pharmacological interactions between Bev and Tem that could explain these good results. If the therapeutic index is ultimately well determined, the antitumor effect of Bev and Tem is very likely to yield fruitful results.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Squamous Cell; Cell Line, Tumor; Female; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Nude; Middle Aged; Molecular Targeted Therapy; Sirolimus; Treatment Outcome; Xenograft Model Antitumor Assays

For patients diagnosed with advanced renal cell carcinoma (RCC), there are few therapeutic options. Radiation therapy is predominantly used to treat metastasis and has not proven effective in the adjuvant setting for renal cancer. Furthermore, RCC is resistant to standard cytotoxic chemotherapies. Targeted anti-angiogenics are the standard of care for RCC but are not curative. Newer agents, such as mTOR inhibitors and others that induce autophagy, have shown great promise for treating RCC. Here, we investigate the potential use of the small molecule STF-62247 to modulate radiation.. Using RCC cell lines, we evaluate sensitivity to radiation in addition to agents that induce autophagic cell death by clonogenic survival assays. Furthermore, these were also tested under physiological oxygen levels.. STF-62247 specifically induces autophagic cell death in cells that have lost VHL, an essential mutation in the development of RCC. Treatment with STF-62247 did not alter cell cycle progression but when combined with radiation increased cell killing under oxic and hypoxic/physiological conditions.. This study highlights the possibility of combining targeted therapeutics such as STF-62247 or temsirolimus with radiation to reduce the reliance on partial or full nephrectomy and improve patient prognosis.

Topics: Antineoplastic Agents; Autophagy; Carcinoma, Renal Cell; Cell Cycle; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Humans; Kidney Neoplasms; Mutation; Pyridines; Radiation Dosage; Radiation Tolerance; Sirolimus; Thiazoles; Tumor Stem Cell Assay; Von Hippel-Lindau Tumor Suppressor Protein

Mst1/Stk4, a hippo-like serine-threonine kinase, is implicated in many cancers, including prostate cancer. However, the mechanisms regulating Mst1 remain obscure. Here, we characterized the effects of phospho-Thr-120 on Mst1 in prostate cancer cells. We demonstrated that phospho-Thr-120 did not alter the nuclear localization or cleavage of Mst1 in a LNCaP or castration-resistant C4-2 prostate tumor cell model, as revealed by a mutagenesis approach. Phospho-Thr-120 appeared to be specific to cancer cells and predominantly localized in the nucleus. In contrast, phospho-Thr-183, a critical regulator of Mst1 cell death, was exclusively found in the cytoplasm. As assessed by immunohistochemistry, a similar distribution of phospho-Mst1-Thr-120/Thr-183 was also observed in a prostate cancer specimen. In addition, the blockade of PI3K signaling by a small molecule inhibitor, LY294002, increased cytoplasmic phospho-Mst1-Thr-183 without having a significant effect on nuclear phospho-Mst1-Thr-120. However, the attenuation of mammalian target of rapamycin (mTOR) activity by a selective pharmacologic inhibitor, Ku0063794 or CCI-779, caused the up-regulation of nuclear phospho-Mst1-Thr-120 without affecting cytoplasmic phospho-Mst1-Thr-183. This suggests that PI3K and mTOR pathway signaling differentially regulate phospho-Mst1-Thr-120/Thr-183. Moreover, mutagenesis and RNAi data revealed that phospho-Thr-120 resulted in C4-2 cell resistance to mTOR inhibition and reduced the Mst1 suppression of cell growth and androgen receptor-driven gene expression. Collectively, these findings indicate that phospho-Thr-120 leads to the loss of Mst1 functions, supporting cancer cell growth and survival.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cell Nucleus; Chromones; HEK293 Cells; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Nude; Morpholines; Neoplasms, Experimental; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; RNA Interference; Signal Transduction; Sirolimus; Threonine; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Tumor Burden

The objectives of this study were (i) to characterize the interaction of vandetanib with P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp1) in vitro and in vivo (ii) to study the modulation of P-gp and BCRP mediated efflux of vandetanib with specific transport inhibitors and m-TOR inhibitors, everolimus and temsirolimus. Cellular accumulation and bi-directional transport studies in MDCKII cell monolayers were conducted to delineate the role of efflux transporters on disposition of vandetanib. Brain distribution studies were conducted in male FVB wild-type mice with vandetanib administered intravenously either alone or in the presence of specific inhibitors and m-TOR inhibitors. In vitro studies suggested that vandetanib is a high affinity substrate of Bcrp1 but is not transported by P-gp. Interestingly, in vivo brain distribution studies in FVB wild type mice indicated that vandetanib penetration into the brain is restricted by both Bcrp1 and P-gp mediated active efflux at the blood brain barrier (BBB). Co-administration of elacridar, a dual P-gp/BCRP inhibitor increased the brain to plasma concentration ratio of vandetanib upto 5 fold. Of the two m-TOR pathway inhibitors examined; everolimus showed potent effect on modulating vandetanib brain penetration whereas no significant affect on vandetanib brain uptake was observed following temsirolimus co-administration. This finding could be clinically relevant as everolimus can provide synergistic pharmacological effect in addition to primary role of vandetanib efflux modulation at BBB for the treatment of brain tumors.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Blood-Brain Barrier; Brain; Cell Line; Dogs; Drug Synergism; Everolimus; Male; Mice; Piperidines; Quinazolines; Sirolimus; Tissue Distribution; TOR Serine-Threonine Kinases

The aim of this study was to determine the stability of ready-to-use temsirolimus infusion solutions under different storage conditions. Solutions were prepared in polypropylene containers by adding temsirolimus injection to 0.9% sodium chloride infusion to reach a final concentration of 100mg/L. The following storage conditions were tested: (i) 4(o)C in the refrigerator; (ii) 20(o)C under room light exposure and light protection; and (iii) outdoor temperature with sunlight exposure. Moreover, stress testing was performed on drug substance at 20(o)C under ultraviolet (UV) radiation (365 nm). A stability-indicating high-performance liquid chromatography (HPLC) method with UV detection was developed for this analysis. Precision was below 4% and accuracy ranged from 97 to 102%. The lower limit of quantitation was 0.1mg/L. The degradation products produced after UV light exposure were detected upon further analysis by mass spectrometry detection. The stability of temsirolimus is light and temperature dependent. After storage at 20(o)C with room light exposure, the rate of degradation was around 0.25%/h; after 1 day, 92.5% of the initial temsirolimus concentration was recovered. When protected from light, at 4 and 20(o)C, losses were decelerated; the decrease in drug concentration was 1.0 and 1.56% per day, respectively. Under daylight exposure, a substantial decrease in drug concentration was observed; after 1h, losses were higher than 10%. Exposed to UV light, half of the drug was lost after 45 min. In conclusion, temsirolimus 100mg/L in infusion polypropylene bags containing 0.9% sodium chloride was chemically stable when protected from light for 4 and 3 days at 4 and 20(o)C, respectively.

Topics: Chromatography, High Pressure Liquid; Drug Packaging; Drug Stability; Drug Storage; Immunosuppressive Agents; Pharmaceutical Solutions; Pharmacy Service, Hospital; Polypropylenes; Reproducibility of Results; Sirolimus; Spectrophotometry, Ultraviolet; Temperature; Ultraviolet Rays

Zwitterionic oligopeptide liposomes (HHG2C(18)-L) containing a smart lipid (1,5-dioctadecyl-L-glutamyl 2-histidyl-hexahydrobenzoic acid, HHG2C(18)) are developed to overcome the barriers faced by anticancer drugs on the route from the site of injection into the body to the final antitumor target within transport steps with multiple physiological and biological barriers. HHG2C(18)-L show the multistage pH-responsive to the tumor cell (the mitochondria in this case). Their multistage pH response leads to more effective entry of the tumor cell, improved escape from the endolysosomes, and accumulation at the mitochondria (see picture).

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Humans; Hydrogen-Ion Concentration; Liposomes; Mice; Mitochondria; Neoplasms; Oligopeptides; Sirolimus; Tissue Distribution; Transplantation, Heterologous

This study was conducted to evaluate the treatment outcomes associated with common second-line targeted therapies given after first-line sunitinib for metastatic renal cell carcinoma (mRCC). The sample comprised patients with mRCC (n = 257) who were receiving second-line everolimus, sorafenib, or temsirolimus between April 1, 2008, and February 29, 2011, after first-line sunitinib treatment. The patients were followed-up from the start of second-line treatment until treatment failure (defined as advancement to a third-line therapy or to mortality) or the last observation in the medical and pharmacy databases. Treatment failure was observed in 38.5% (n = 99) of cases: 20.2% of patients (n = 52) advanced a line of treatment; and 18.3% of patients (n = 47) died. Kaplan-Meier analysis indicated a statistical difference in time to treatment failure among the 3 second-line targeted therapies (log-rank test, P = .045). The estimated 1-year cumulative probabilities of treatment failure were 49.9% for everolimus, 68.4% for sorafenib, and 71.4% for temsirolimus. In a multivariate Cox proportional hazards model, a higher adjusted risk of treatment failure vs. everolimus was observed for both temsirolimus (hazard ratio [HR] 2.05 [95% CI, 1.26-3.35]; P = .004) and sorafenib (HR 1.77 [95% CI, 1.02-3.07]; P = .043). The results of this real-world data analysis suggest that the risk of second-line treatment failure after first-line sunitinib was significantly higher with temsirolimus and sorafenib compared with everolimus.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Gastrointestinal Neoplasms; Humans; Indoles; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Pyrroles; Sirolimus; Somatostatin; Sunitinib

Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause a diverse range of diseases collectively called laminopathies, the most common of which is dilated cardiomyopathy. Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways, but the specific mechanisms are poorly understood. We show that the AKT-mammalian target of rapamycin pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function. We also show defective autophagy in hearts of these mice and demonstrate that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy. These findings provide a rationale for treatment of LMNA cardiomyopathy with rapalogs and implicate defective autophagy as a pathogenic mechanism of cardiomyopathy arising from LMNA mutation.

Topics: Animals; Autophagy; Cardiomyopathies; Lamin Type A; Mutation; Rats; Sirolimus

The mammalian target of rapamycin signaling pathway has been implicated in therapeutic resistance in several types of cancer. However, the significance of mammalian target of rapamycin activation in chemoradiotherapy sensitivity and its effect on the prognosis of esophageal squamous cell carcinoma treated with chemoradiotherapy remain unknown. However, this pathway is of particular interest because an effective inhibitor is available.. By using immunohistochemistry, phosphorylated mammalian target of rapamycin expression was examined in 77 patients with esophageal squamous cell carcinoma treated with preoperative chemoradiotherapy followed by surgery between 1999 and 2009, and correlated with treatment outcome. With the use of CE81T/VGH and TE2 cell lines, cells were treated with chemotherapy, temsirolimus (mammalian target of rapamycin inhibitor), or a combination of chemotherapy and temsirolimus, and investigated by 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.. Pathologic complete response rates were 42% and 16% in patients with negative and positive phosphorylated mammalian target of rapamycin expression, respectively (P = .01). The 3-year overall survivals were 57% and 30% in patients with negative and positive phosphorylated mammalian target of rapamycin expression, respectively (P = .005). Positive phosphorylated mammalian target of rapamycin expression was independently associated with inferior overall and disease-free survival. In patients who did not achieve pathologic complete response, postchemoradiotherapy esophagectomy specimens showed significantly higher phosphorylated mammalian target of rapamycin expression than pretreatment biopsy specimens. In cell lines, concomitant administration of temsirolimus enhanced the effect of chemotherapy.. Phosphorylated mammalian target of rapamycin expression is independently associated with the response to chemoradiotherapy and prognosis of patients with esophageal squamous cell carcinoma treated with preoperative chemoradiotherapy. Mammalian target of rapamycin inhibition can sensitize esophageal cancer cells to chemotherapy. Our results suggest the potential for mammalian target of rapamycin as a therapeutic target for patients with esophageal squamous cell carcinoma who receive multimodality treatment.

Topics: Adult; Aged; Biomarkers, Tumor; Biopsy; Carcinoma, Squamous Cell; Cell Line, Tumor; Chemoradiotherapy, Adjuvant; Chi-Square Distribution; Disease-Free Survival; Esophageal Neoplasms; Esophagectomy; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Odds Ratio; Phosphorylation; Proportional Hazards Models; Protein Kinase Inhibitors; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome

The sarcomatoid variant of metastatic renal cell carcinoma (RCC) has often an aggressive course and a poor prognosis, particularly when accompanied with brain metastasis.. We describe the case of a patient with sarcomatoid variant RCC in whom brain metastasis was observed as a new lesion during treatment with temsirolimus, despite other extracerebral metastatic lesions being well-controlled and progression-free.. This discrepancy between the effectiveness of temsirolimus for extracerebral metastases and the simultaneous progression of brain metastases of RCC raises a concern that while vascular endothelial growth factor (VEGF)-targeted therapy may have clinical efficacy, it may also carry a risk for new brain metastases due to weakening of the structure of the blood brain barrier.. This case indicates that computed tomography monitoring of the brain should be regularly performed during VEGF-targeted therapy in patients with sarcomatoid variant RCC, even if brain metastases are absent and extracerebral metastatic lesions are well controlled.

Topics: Antineoplastic Agents; Brain Neoplasms; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Neoplasm Metastasis; Sirolimus

Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)-containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor.. We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS).. Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514).. Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Pharmacological; Carcinoma, Renal Cell; Female; Humans; Interferon-alpha; Kidney Neoplasms; L-Lactate Dehydrogenase; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Transcription Factors

The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer.. Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated.. Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression.. SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.

Topics: Animals; Cell Line, Tumor; Chemokine CXCL12; Cyclin D1; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Pyridines; Quinazolines; Receptors, CXCR; Receptors, CXCR4; RNA Interference; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Topics: Carcinoma, Renal Cell; Humans; Indoles; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prognosis; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Survival Analysis

Topics: Antineoplastic Agents; Erlotinib Hydrochloride; Everolimus; Gefitinib; Humans; Lung Diseases; Quinazolines; Sirolimus

We analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in metastatic RCC (mRCC) treated with or without anti-angiogenic agents (AA).. Data from all consecutive metastatic RCC patients (patients) treated in a french cancer center between 1995 and 2008 were reviewed. Patients had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. AA were sorafenib, sunitinib and bevacizumab. We also included patients treated with mTor inhibitors, temsirolimus and everolimus, as they also demonstrated anti-angiogenic activities. Characteristics of the two groups treated with or without AA were compared with a Fisher exact test. Impact of AA on overall survival (OS) and cumulative rate of brain metastasis (CRBM) was explored by Kaplan-Meier method.. One hundred and ninety-nine patients with advanced RCC were identified, 51 treated with AA and 148 without AA. The median follow-up duration was 40 months. BM occurred in 35 patients. Characteristics between AA treated and non-AA treated groups were unbalanced and favoring better prognostic factors in AA treated group. Median OS was 24 months. AA treatment was not associated with a lower CRBM (HR = 0.58 [0.26-1.30], P = 0.187). Median survival free of BM was 11.8 months, CI95% (4.95-18.65) in the group without AA treatment and 28.9 months in the AA group, CI95% (18.64-39.16). Alkaline phosphatase (AP) was an independent prognostic factor for BM (P = 0.05). In multivariate Cox model, after adjustment to AP, AA did not improve the CRBM (aHR = 0.53 [0.22-1.32]).. In this retrospective study, AA did not decrease significantly the CRBM. Elevated AP was a predictive factor for BM in mRCC.

Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Brain Neoplasms; Cancer Care Facilities; Carcinoma, Renal Cell; Everolimus; Female; France; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Pyridines; Pyrroles; Retrospective Studies; Risk Factors; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

Surgical excision is the gold standard therapy for clinically localized renal masses. Nevertheless, prognostication of the natural history of untreated renal cell carcinoma (RCC) remains a clinical challenge. While active surveillance (AS) has emerged as a viable treatment option in select patients with localized tumors and significant competing mortality risks, long term follow up data to assess the risk of disease progression are limited. We present a case of a localized, clinical stage T2 renal mass progressing to regional and systemic disease over 6 years, demonstrating that kinetics of disease progression may be prolonged and are yet to be fully understood.

Topics: Aged; Biopsy, Needle; Brain Neoplasms; Carcinoma, Renal Cell; Disease Progression; Drug Delivery Systems; Follow-Up Studies; Humans; Immunohistochemistry; Kidney Neoplasms; Lymph Node Excision; Lymph Nodes; Male; Neoplasm Staging; Nephrectomy; Risk Assessment; Sirolimus; Time Factors; Tomography, X-Ray Computed

Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream effectors, Akt and mechanistic target of rapamycin (mTOR), is aberrantly activated in acute myeloid leukemia (AML) patients, where it contributes to leukemic cell proliferation, survival, and drug-resistance. Thus, inhibiting mTOR signaling in AML blasts could enhance their sensitivity to cytotoxic agents. Preclinical data also suggest that allosteric mTOR inhibition with rapamycin impaired leukemia initiating cells (LICs) function. In this study, we assessed the therapeutic potential of a combination consisting of temsirolimus [an allosteric mTOR complex 1 (mTORC1) inhibitor] with clofarabine, a nucleoside analogue with potent inhibitory effects on both ribonucleotide reductase and DNA polymerase. The drug combination (CLO-TOR) displayed synergistic cytotoxic effects against a panel of AML cell lines and primary cells from AML patients. Treatment with CLO-TOR induced a G₀/G₁-phase cell cycle arrest, apoptosis, and autophagy. CLO-TOR was pro-apoptotic in an AML patient blast subset (CD34⁺/CD38⁻/CD123⁺), which is enriched in putative leukemia initiating cells (LICs). In summary, the CLO-TOR combination could represent a novel valuable treatment for AML patients, also in light of its efficacy against LICs.

Topics: Adenine Nucleotides; ADP-ribosyl Cyclase 1; Allosteric Regulation; Antigens, CD34; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arabinonucleosides; Autophagy; Cell Line, Tumor; Clofarabine; Dose-Response Relationship, Drug; Drug Synergism; Eukaryotic Initiation Factor-4F; Extracellular Signal-Regulated MAP Kinases; G1 Phase Cell Cycle Checkpoints; Humans; Interleukin-3 Receptor alpha Subunit; Leukemia, Myeloid, Acute; Membrane Glycoproteins; Phosphatidylinositol 3-Kinase; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; STAT3 Transcription Factor; Time Factors; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Prednisolone; Remission Induction; Sirolimus; Tongue Neoplasms; Treatment Failure; Treatment Outcome; Vincristine

Temsirolimus is an i.v. administered inhibitor of mammalian target of rapamycin with activity in the first-line setting in poor-prognosis patients with metastatic renal cell carcinoma (RCC). The efficacy of this agent after failure of prior inhibitors of vascular endothelial growth factor (VEGF) is unknown.. a retrospective review of patients with metastatic RCC treated at the Cleveland Clinic Taussig Cancer Institute and three regional cancer centers in Ontario, Canada, through the Torisel (temsirolimus) Compassionate Use Program was conducted. Demographic, toxicity and response data were collected.. a total of 87 patients with metastatic RCC were identified who had previously been treated with inhibitors of VEGF subsequently treated with temsirolimus. The majority of patients had either intermediate or poor-prognosis disease at baseline. Expected toxic effects including hyperglycemia and noninfectious pneumonitis were observed. The RECIST-defined objective response rate was 5% and the stable disease rate was 65%. The median time to progression (TTP) was 3.9 months (95% confidence interval 2.8-4.8 months), and median overall survival was 11.2 months.. in a cohort of pre-treated intermediate to poor-prognosis patients with metastatic RCC, weekly i.v. temsirolimus is associated with predictable, but manageable toxicity, and a TTP approaching 4 months.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Compassionate Use Trials; Drug Resistance, Neoplasm; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; Vascular Endothelial Growth Factor A

Reactivation of tuberculosis is rare in patients receiving chemotherapy for solid tumours, and poorly documented in patients receiving molecular targeted therapy. We report on a patient with metastatic renal-cell carcinoma treated with temsirolimus, who developed respiratory symptoms and mild fever after 6 weeks of treatment. CT-scan and laboratory tests were consistent with reactivation of tuberculosis. The patient received anti-tuberculosis therapy including rifampicin, a potent CYP3A4/5 inducer. After introduction of rifampicin-based treatment, the patient experienced tumour progression, leaving questionable the potential pharmacokinetic interaction between rifampicin and temsirolimus, a substrate for CYP3A4.

Topics: Aged, 80 and over; Antibiotics, Antitubercular; Antineoplastic Agents; Carcinoma, Renal Cell; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Induction; Humans; Kidney Neoplasms; Male; Neoplasm Metastasis; Rifampin; Sirolimus; Tuberculosis

Bladder cancer and head and neck squamous cell carcinoma (HNSCC) are frequent but lack efficient therapies especially in advanced disease. Almost no studies on mTOR function and inhibition in these tumor entities have been reported. We examined the gene and protein expression levels of mTOR and its activated form (pmTOR) in three human bladder carcinoma cell lines (RT-4, T24, EJ28) and three HNSCC cell lines (PCI-1, PCI-13, BHY). Furthermore, the consequences of mTOR inhibition by mTOR-specific siRNAs and the mTOR inhibitor temsirolimus were analysed in vitro using immunohistochemical Ki-67 staining, mTOR and pmTOR western blot analysis, MTT assay, as well as cell cycle analysis with flow cytometry. Especially pmTOR protein expression levels showed marked differences between cell lines. siRNA transfection was associated with dose-dependent target protein reduction but not proliferation inhibition or apoptosis. On the contrary, temsirolimus significantly reduced cell viability and induced apoptosis and cell cycle arrest. According to these data, bladder cancer and HNSCC are promising tumor entities for mTOR inhibition with temsirolimus.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Cycle; Cell Proliferation; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Protein Kinase Inhibitors; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Urinary Bladder Neoplasms

Clear cell carcinoma (CCC) of the ovary is well-known to be chemotherapy resistant compared with other histologic subtypes. An inhibitor against the mammalian target of rapamycin, temsirolimus (TEM) has been reported to be effective in renal CCC. Therefore, we investigated the effects of TEM in patients with CCC of the ovary. Six patients with CCC of the ovary who had been heavily pretreated by more than 4 regimens were given TEM: the cycle consisted of weekly TEM (10 mg/m(2)) for 3 weeks followed by 1 week off. The treatment was continued until development of either progressive disease, or unmanageable adverse effects. Response evaluation was based upon the Response Evaluation Criteria in Solid Tumors version 1.0. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events version 3.0. The median cycle of weekly TEM was 3 (range 2-14). Among five cases in which responses could be evaluated, partial response was observed in one case (20%) and stabilized disease was seen in another case (20%). There were no toxicities greater than grade 3, and no case developed severe toxicity requiring discontinuation of weekly TEM. The patient who showed a partial response obtained a progression-free period of 14 months. In conclusion, weekly TEM shows a potential therapeutic benefit for patients with CCC of the ovary. Further studies including a translational approach are needed to select candidates for whom TEM therapy would be beneficial.

Topics: Adenocarcinoma, Clear Cell; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CA-125 Antigen; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Sirolimus

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biopsy; Female; Humans; Lymphangioleiomyomatosis; Middle Aged; Protein Kinase Inhibitors; Retroperitoneal Neoplasms; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome

To report our experience with temsirolimus in 2nd-, 3rd- and 4th-line therapy for patients with metastatic renal cell carcinoma (mRCC).. In our prospectively maintained tumor registry, we identified 6 mRCC patients with temsirolimus in >1st-line systemic therapy. Patients were followed by weekly clinical and laboratory examination during admission of temsirolimus. Re-staging with chest CT and abdominal MRI was performed every 3 months.. We observed excellent response rates. Progression-free survival (PFS) ranged from 6 to 40 months with a median of 15 months. Treatment was generally well tolerated. However, pneumonitis was observed in 4 of 6 patients. Drug-related pneumonitis led to severe dyspnea, with the result that treatment with temsirolimus had to be interrupted for a short period of time in 2 patients and discontinued in 1 patient.. Temsirolimus proved to be a very good treatment option in 2nd- to 4th-line therapy with excellent response rates and manageable side effects. The incidence of pneumonitis must not be underestimated.

Topics: Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Medical Oncology; Neoplasm Metastasis; Pneumonia; Prospective Studies; Registries; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Aberrant PDGFR signaling is observed in approximately 25-30% of human GBMs, which are frequently molecularly classified as the proneural subclass. It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition.. Using genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM that closely mimic the histology and genetics of the human PDGF subgroup, we investigated the effect of inhibiting Akt and mTOR alone or in combination in vitro and in vivo. We used perifosine and CCI-779 to inhibit Akt and mTOR, respectively. Here, we show in vitro data demonstrating that the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null primary glioma cell cultures is obtained when using both inhibitors in combination. We next investigated if the effects we observed in culture could be duplicated in vivo by treating mice with gliomas for 5 days. The in vivo treatments with the combination of CCI-779 and perifosine resulted in decreased Akt and mTOR signaling, which correlated to decreased proliferation and increased cell death independent of PTEN status, as monitored by immunoblot analysis, histology and MRI.. These findings underline the importance of simultaneously targeting Akt and mTOR to achieve significant down-regulation of the PI3K pathway and support the rationale for testing the perifosine and CCI-779 combination in the human PDGF-subgroup of GBM.

Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Synergism; Glioblastoma; Mice; Phosphatidylinositol 3-Kinases; Phosphorylcholine; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Sirolimus

Chromophobe renal cell carcinoma (chRCC) is a common subtype of renal cell carcinoma (RCC), occurring in 6-11% of renal carcinoma patients. Limited clinical trial data have shown minimal activity with cytokines and chemotherapy, although small-molecule inhibitors of the vascular endothelial growth factor and platelet-derived growth factor pathways such as sunitinib and sorafenib, which are associated with significant clinical activity in clear-cell RCC (ccRCC), have been associated with a 25% response rate in chRCC. The mammalian target of rapamycin kinase inhibitor temsirolimus demonstrates good clinical activity in ccRCC patients with poor prognosis, with further data suggesting it is an effective treatment for all RCC tumour histologies. This report describes the case of a patient with chRCC who experienced rapid improvement in his general condition and stable disease on treatment with temsirolimus, following disease progression on interferon alfa and sorafenib treatment. This case report suggests that temsirolimus is an effective and appropriate treatment for this RCC tumour subtype.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Humans; Interferons; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Salvage Therapy; Sirolimus; Sorafenib; Treatment Outcome

Rationally designed therapies aim at the specific disruption of critical signaling pathways activated by malignant transformation or signals from the tumor microenvironment. Because mammalian target of rapamycin (mTOR) is an important signal integrator and a key translational regulator, we evaluated its potential involvement in T-cell acute lymphoblastic leukemia (T-ALL) and whether mTOR blockade synergizes with chemotherapeutic agents or other signaling antagonists to inhibit primary leukemia T cells.. mTOR signaling status was assessed using biochemical, immunostaining, and molecular regulation studies and functional assays performed to assess the impact of mTOR blockade on T-ALL proliferation, survival, and cell cycle.. We observed that mTOR signaling is highly activated in all T-ALL patients tested, with phosphorylation of its downstream substrates eIF4G and S6 ribosomal protein. mTOR activation was detected in vivo and was further increased in vitro by stimulation with interleukin-7, a potentially leukemogenic cytokine normally produced by the bone marrow microenvironment. In T-ALL cells, mTOR blockade was associated with accumulation of the cyclin-dependent kinase inhibitor p27(kip1), which preferentially adopted a nuclear localization. Functional studies using rapamycin or CCI-779 showed a dominant inhibitory effect of mTOR blockade on interleukin-7-induced proliferation, survival, and cell-cycle progression of T-ALL cells. Furthermore, mTOR blockade markedly potentiated the antileukemia effects of dexamethasone and doxorubicin, and showed highly synergistic interactions in combination with specific inhibitors of phosphatidylinositol 3-kinase/Akt and Janus kinase 3 signaling.. This study shows activation of mTOR signaling in primary T-ALL cells evolving in the leukemic bone marrow, and supports the inclusion of mTOR antagonists in current therapeutic regimens for this cancer.

Topics: Antibiotics, Antineoplastic; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromones; Dexamethasone; Doxorubicin; Drug Synergism; Enzyme Inhibitors; Eukaryotic Initiation Factor-4G; Humans; Immunoblotting; Immunohistochemistry; Janus Kinase 3; Microscopy, Fluorescence; Morpholines; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-akt; Quinazolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Aged; Everolimus; Female; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Radiotherapy; Sirolimus; TOR Serine-Threonine Kinases

Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor and rapamycin analogue that is approved for treating advanced renal cell carcinoma (RCC). It is being actively evaluated in clinical trials for melanoma. The mTOR inhibitors are also immunosuppressants and are used clinically to prevent rejection following solid-organ transplant. Novel immunotherapies are being actively developed for immunoresponsive tumours, such as RCC and melanoma.. Immune-modulating effects of temsirolimus were characterised when used in combination with cancer vaccines targeting RCC (RENCA) and melanoma (B16). Cancer vaccines were recombinant tumour-specific proteins (CA9 or gp100), and recombinant heat shock protein (HSP; hsp110) served as the immune adjuvant.. In murine models, temsirolimus enhanced the anti-tumour activity of cancer vaccines used to treat established RENCA and B16 tumours. A tumour prevention model established that the enhanced anti-tumour activity associated with temsirolimus was immune mediated. In mice treated with an HSP-based anti-tumour vaccine, temsirolimus-treated CD8 T cells had greater interferon-γ and cytotoxic T-cell responses when compared with mice treated with vaccine alone. Temsirolimus also enhanced the formation of CD8 memory cells following administration of HSP-based cancer vaccine.. These results provide a rationale for combining mTOR inhibitor with immunotherapy when treating immunoresponsive tumours.

Topics: Animals; Antineoplastic Agents; Cancer Vaccines; Carcinoma, Renal Cell; Cells, Cultured; Drug Synergism; Heat-Shock Proteins; Immunosuppressive Agents; Immunotherapy; Kidney Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

The phosphoinositide 3-kinase (PI3K)/Akt pathway is widely postulated to be an effective therapeutic target in thyroid cancer.. The aim of the study was to test the therapeutic potential of the novel Akt inhibitor MK2206 for thyroid cancer.. We examined the effects of MK2206 on thyroid cancer cells with respect to the genotypes of the PI3K/Akt pathway.. Proliferation of thyroid cancer cells OCUT1, K1, FTC133, C643, Hth7, and TPC1, which harbored PIK3CA, PTEN, Ras, or RET/PTC mutations that could activate the PI3K/Akt pathway, was potently inhibited by MK2206 with IC(50) values mostly below or around 0.5 μm. In contrast, no potent inhibition by MK2206 was seen in most of the Hth74, KAT18, SW1736, WRO, and TAD2 cells that did not harbor mutations in the PI3K/Akt pathway. The inhibition efficacy was also genetic-selective. Specifically, the average inhibition efficacies were 59.2 ± 11.3 vs. 36.4 ± 8.8% (P = 0.005) at 1 μm MK2206 and 64.4 ± 11.5 vs. 38.5 ± 18.9% (P = 0.02) at 3 μm MK2206 for cells with mutations vs. cells without. The SW1736 cell, lacking mutations in the PI3K/Akt pathway, had minimal response to MK2206, but transfection with exogenous PIK3CA mutants, PIK3CA H1047R and E545K, significantly increased its sensitivity to MK2206. MK2206 also completely overcame the feedback activation of Akt from temsirolimus-induced mammalian target of rapamycin suppression, and the two inhibitors synergistically inhibited thyroid cancer cell growth.. Our study demonstrates a genetic selectivity of MK2206 in inhibiting thyroid cancer cells by targeting the PI3K/Akt pathway, supporting a clinical trial in thyroid cancer.

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Evaluation, Preclinical; Drug Synergism; Heterocyclic Compounds, 3-Ring; Humans; Phosphatidylinositol 3-Kinases; Phosphorylation; Point Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; Substrate Specificity; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Preclinical data have indicated that alteration of PTEN and activation of the mammalian target of rapamycin (mTOR) pathway play a crucial role in the oncogenesis of leiomyosarcoma. The objective of this exploratory study was to assess the clinical role of mTOR inhibition in patients with advanced leiomyosarcoma refractory to standard chemotherapy. Patients with advanced leiomyosarcoma were treated with temsirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined according to the response evaluation criteria in solid tumor (RECIST) and Choi criteria. Tumors were assessed for immunohistochemical evidence of PTEN loss of expression and mTOR activation. Six patients participated in the study. According to the RECIST, three patients had stable disease and three patients had progressive disease. The three patients with RECIST stable disease had partial response according to the Choi criteria. Partial response according to the Choi criteria was associated with clinical improvement and biological signs of temsirolimus antitumor activity. The immunohistochemical status of PTEN and phosphorylated S6 ribosomal protein was not predictive of the outcome. This exploratory study indicates antitumor activity of temsirolimus in leiomyosarcoma, possibly through a mechanism involving aberration of the PTEN gene. Further investigations of the phosphoinositide 3-kinases/PTEN/Akt/mTOR pathway are needed to explore the role of mTOR inhibitors, either alone or in combination, in patients with advanced sarcoma.

Topics: Adult; Antineoplastic Agents; Female; Humans; Leiomyosarcoma; Male; Middle Aged; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Ribosomal Protein S6; Signal Transduction; Sirolimus; Statistics as Topic; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Aged; Aged, 80 and over; Carcinoma, Renal Cell; Enteritis; Everolimus; Female; Humans; Kidney Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Sirolimus; TOR Serine-Threonine Kinases

Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy.. Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin.. Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin.. The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Cycle; Cell Proliferation; Cisplatin; Drug Synergism; Feasibility Studies; Female; Humans; Immunoenzyme Techniques; In Situ Nick-End Labeling; In Vitro Techniques; Mesothelioma; Mice; Mice, SCID; Pleural Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sirolimus; Spheroids, Cellular; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

This post hoc analysis evaluated treatment-associated quality-adjusted survival (QAS) in patients randomly assigned to temsirolimus or interferon alfa (IFN-alfa), corrected for censoring using inverse probability weighting (IPW), in the Advanced Renal Cell Carcinoma (ARCC) trial.. Follow-up was divided into 11 time intervals; Kaplan-Meier estimates for not being censored were estimated for each interval. The QAS for each interval was weighted by the inverse probability of not being censored in that interval. Overall treatment-associated QAS was calculated as the sum of the weighted QAS across all follow-up intervals. Differences in mean QAS between temsirolimus and IFN-alfa were evaluated with t-statistics at a two-sided α = 0.05.. In total, 416 patients were randomly assigned to temsirolimus (n = 209) or IFN-alfa (n = 207); 400 patients were included in this analysis. Overall weighted mean (standard deviation) QAS during progression-free survival was 111.9 (5.3) days with temsirolimus (n = 204) and 75.7 (6.3) days with IFN-alfa (n = 196). The mean weighted QAS difference of 36.2 days in favor of temsirolimus was significant (p < 0.05).. One potential limitation is that the weights developed by the Kaplan-Meier estimates did not allow for covariates to be adjusted among treatment arms. Another possible limitation is that the ARCC trial included patients with advanced renal cell carcinoma, and thus it cannot be conclusively determined how our findings would apply to patients with less advanced disease.. Patients with poor-prognosis advanced renal cell carcinoma treated with temsirolimus had an incremental gain of 48% (36.2 days) in QAS compared with patients treated with IFN-alfa.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Female; Humans; Immunologic Factors; Interferon-alpha; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Probability; Prognosis; Psychometrics; Quality-Adjusted Life Years; Sirolimus; United States; Young Adult

We previously reported on head and neck tumor xenografts that the tumor regression induced by a triple combination of irradiation (RT), anti-EGFR and anti-angiogenic therapies was followed, after treatment arrest, by tumor re-growth characterized by activation of the AKT signaling pathway. Since mTOR is the main AKT-related messenger, the aim of this study was to add the mTOR inhibitor temsirolimus to a tri-therapy with RT plus anti-EGFR and anti-angiogenic drugs in order to improve anti-tumor effects. The human head and neck cancer cell line CAL33 (over-expressing EGFR and secreting VEGF-A) was xenografted in nude mice. Treatment (20 mice per treatment group) was administered for 2 weeks and consisted of either vehicle (control), temsirolimus (5mg/kg i.p. five times a week), tri-therapy with RT (6 Gy three times a week) combined with cetuximab (0.5mg/kg i.p. five times a week) and bevacizumab (5mg/kg i.p. five times a week) or the temsirolimus-tri-therapy association. The time to reach a tumor volume of 2000 mm(3) was significantly different between the four treatment groups (Log Rank p<0.0001), with a median of 29.5, 44.5, 67.0 and 70.0 days for control, temsirolimus, tri-therapy and combination groups, respectively. The combination of temsirolimus plus tri-therapy produced the longest growth-inhibiting effects (tri-therapy versus combination, p=0.01). No significant interaction was observed between temsirolimus and the tri-therapy, suggesting that temsirolimus, on the one hand, and RT-cetuximab-bevacizumab, on the other, exert additive effects on tumor growth inhibition. These decreases observed on tumor growth were corroborated by the parallel decreases observed on tumor proliferation (Ki67) and on anti-apoptotic markers (Bcl2). These results suggest that temsirolimus exhibits synergistic antiproliferative effects when administered in combination with irradiation, anti-EGFR and anti-angiogenic therapies in head and neck cancer patients.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma, Squamous Cell; Cell Line, Tumor; Cetuximab; Combined Modality Therapy; Drug Synergism; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Homotemsirolimuses A, B, and C (2a, 2b, 2c) were found to be minor components of a temsirolimus preparation made from rapamycin. These three temsirolimus analogues are derived from the corresponding rapamycin analogues, homorapamycins A, B, and C (1a, 1b, 1c) produced by the strain Streptomyces hygroscopicus. The structures of homotemsirolimuses A, B, and C were determined by spectroscopic methods. These compounds were tested for mTOR kinase inhibition and in two proliferation assays using LNCap prostate and MDA468 breast cancer cells. The results suggested that the mTOR inhibition and antiproliferation potencies for 2a, 2b, and 2c are comparable to those of rapamycin (1) and temsirolimus (2).

Topics: Antineoplastic Agents; Drug Screening Assays, Antitumor; Female; Humans; Male; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Sirolimus; Streptomyces; Tacrolimus Binding Proteins; TOR Serine-Threonine Kinases

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoma, Mantle-Cell; Rituximab; Sirolimus

Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize temsirolimus-related pneumonitis.. Patients were treated with intravenous temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method.. Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank P < .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed temsirolimus-related pneumonitis in 16 (31%) of 52 patients.. Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Incidence; Interferon-alpha; Kidney Neoplasms; Pneumonia; Randomized Controlled Trials as Topic; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases

Bellini's renal cell collecting duct carcinoma is a rarely prevalent renal tumour, with low cancer-specific survival, although its rate of response to antiangiogenic therapies is unknown.. We retrospectively revise a series of collecting duct tumours, with special emphasis on the indication of target therapies and on their results.. Retrospective analysis of renal cell collecting duct carcinoma treated at our institution from January 2000 to June 2010, taking into account the patient's age, sex, reason for the consultation, oncological background, side of the affection, surgical treatment, other anatomopathological characteristics, tumour size, TNM clinical staging (2009), adjuvant treatment and survival time.. Six patients are described, five men and one woman, with a mean age of 75 (± 7.7) years. Four of them (66.6%) presented disseminated disease upon diagnosis. Five (83%) were treated with radical nephrectomy and three (50%) received systemic adjuvant treatment, without response. The means survival was 5.5 months (4.75-14.75). Only 2 patients (33.3%), both with localized disease upon diagnosis, are in complete remission.. Renal cell collecting duct carcinoma is a disease with a bad prognosis, little survival and bad response to target therapies.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Deoxycytidine; Female; Gemcitabine; Humans; Incidental Findings; Kidney Neoplasms; Kidney Tubules, Collecting; Male; Neoplasm Staging; Nephrectomy; Prognosis; Retrospective Studies; Sirolimus; Survival Analysis

A characteristic cutaneous eruption related to the use of cytostatic chemotherapeutic drugs has been described in the literature. This condition appears to be characterized by an erythematous eruption, primarily affecting the intertriginous areas bilaterally, together with eccrine squamous syringometaplasia as the main histologic feature.. We sought to establish the epidemiologic, clinical, and histologic characteristics of this poorly defined chemotherapy drug-related eruption.. Retrospective data were collected from 21 consecutive patients with this clinical and histopathologic pattern who attended an oncology center between January 1999 and September 2009. Two skin biopsy specimens were obtained from all patients, with the first being taken within 24 hours of onset, and the second 72 to 96 hours after onset.. The patients analyzed were predominantly female (72%), with a mean age of 52 years (range 10-69 years). The lesions presented clinically as bilateral erythematous plaques affecting both axillae (95%), groin (88%), and side aspects of the neck (48%). The main histologic feature in all cases was eccrine squamous syringometaplasia, characterized by the transformation of the eccrine cuboidal epithelium into two or more layers of squamous cells with intercellular bridges. The onset of the eruption appeared within 30 days (range 2-30 days) after the initiation of the cytostatic agent infusion. The lesions resolved with desquamation and postinflammatory hyperpigmentation. The same cutaneous pattern recurred in up to 50% of patients in whom the oncologist reintroduced the cytostatic treatment.. Small sample size was a limitation.. We suggest the term "chemotherapy-related bilateral dermatitis associated with eccrine squamous syringometaplasia" to describe this distinctive entity, which is primarily associated with pegylated liposomal doxorubicin infusions and chemotherapeutic regimens used in autologous bone-marrow transplantation.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Axilla; Child; Cytostatic Agents; Dermatitis; Doxorubicin; Drug Eruptions; Eccrine Glands; Female; Groin; Humans; Liposomes; Male; Middle Aged; Neck; Retrospective Studies; Sirolimus; Young Adult

To evaluate antitumor efficacy of the generic mammalian target of rapamycin (mTOR) inhibitor sirolimus in preclinical animal models of head and neck squamous cell carcinoma (HNSCC) and compare its effects with those of the patented analogue temsirolimus.. In vivo study.. To develop xenograft established tumor model (ETM) of HNSCC, FaDu cells were injected subcutaneously into nude mice. When tumors reached 50 to 60 mm(3), mice were randomized into five groups and treated daily intraperitoneally with sirolimus at various doses for 5 days per week for 3 weeks. Tumor volumes were measured. The results were compared with historical data on temsirolimus effects. In the minimal residual disease (MRD) model, surgical wounds were created and FaDu cells implanted. After 72 hours, animals were randomized into two groups and were injected intraperitoneally with 0 or 5 mg/kg sirolimus for 5 days per week for 30 days.. In the ETM, sirolimus significantly inhibited tumor growth (P < .01), although there was no overall significant difference in tumor growth inhibition between sirolimus and temsirolimus. In the MRD model, sirolimus significantly suppressed growth of tumors (P < .001) and improved survival compared with controls (P < .01). There was a significant decrease in pS6 expression, indicating mTOR inhibition.. In this study, we demonstrate that the generic mTOR inhibitor sirolimus shows potent antitumor activity in HNSCC and produces comparable effects to the patent drug temsirolimus. Sirolimus has the potential of serving as an economic and comparative targeted agent to temsirolimus in the treatment of HNSCC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Disease Models, Animal; Head and Neck Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Sirolimus

Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of <1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0) /G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3) ; P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; G1 Phase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Pleural Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Since 2006 in Germany six different target drugs for therapy in metastatic renal cell cancer (mRCC) have been used. Comparative studies for the application with the same indication are absent, and the order of potential sequential therapy is up to now unclear. The aim of the study was to collect data on therapy decisions in Germany regarding mRCC in the age of "targeted therapy". At the same time the study addressed the central question of sequencing of the different therapy options. In addition, the data of this study were to be compared to a study already published in 2008.. In 2010, four groups of doctors specialized in the therapy of patients with mRCC were asked for their behaviour in the first-, second- and third-line or sequential therapy. Those questioned included urologists in private practice (n=40), oncologists in private practice (n=40), hospital urologists (n=35) and hospital oncologists (n=35). Further the reasons for a therapy decision should be stated or weighted.. Altogether 92% of all patients with mRCC were treated. Urologists in private practice treat only 30% of their patients themselves. The earlier used immune therapies (IFN, IL-2) no longer play a role. Sunitinib is used most often in first-line therapy by urologists in private practice (50.4%) and oncologists in private practice (47.1%). In second- and third-line therapy everolimus is used by urologists in private practice (27.1%, 26.3%) and sorafenib (28.6%) or everolimus (26.4%) by oncologists in private practice. Hospital oncologists use primarily sunitinib (56.1%), in second-line sorafenib (45.5%) and in third-line above all everolimus (19.4%). Hospital urologists use sunitinib most often for first-line therapy (57.6%) and sorafenib for second-line treatment (37.3%), while in third-line therapy temsirolimus (49.6%) and also everolimus (30.4%) were used.. The therapy of mRCC is determined very strongly by the substances sunitinib and sorafenib. The mTOR inhibitors have recently been increasingly included in the second- and third-line therapy. With the introduction of the new targeted therapies, the treatment of these special patients is performed less by urologists and increasingly more by oncologists. This trend is strengthened in comparison to the DGFIT study from 2008.

Topics: Adult; Aged; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Data Collection; Disease Progression; Drug Delivery Systems; Everolimus; Female; Germany; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Practice Patterns, Physicians'; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases

The cell-cycle G(2)-M phase gene UBE2C is overexpressed in various solid tumors including castration-resistant prostate cancer (CRPC). Our recent studies found UBE2C to be a CRPC-specific androgen receptor (AR) target gene that is necessary for CRPC growth, providing a potential novel target for therapeutic intervention. In this study, we showed that the G(1)-S cell-cycle inhibitor-779 (CCI-779), an mTOR inhibitor, inhibited UBE2C mRNA and protein expression in AR-positive CRPC cell models abl and C4-2B. Treatment with CCI-779 significantly decreased abl cell proliferation in vitro and in vivo through inhibition of cell-cycle progression of both G(2)-M and G(1)-S phases. In addition, exposure of abl and C4-2B cells to CCI-779 also decreased UBE2C-dependent cell invasion. The molecular mechanisms for CCI-779 inhibition of UBE2C gene expression involved a decreased binding of AR coactivators SRC1, SRC3, p300, and MED1 to the UBE2C enhancers, leading to a reduction in RNA polymerase II loading to the UBE2C promoter, and attenuation of UBE2C mRNA stability. Our data suggest that, in addition to its ability to block cell-cycle G(1) to S-phase transition, CCI-779 causes a cell-cycle G(2)-M accumulation and an inhibition of cell invasion through a novel UBE2C-dependent mechanism, which contributes to antitumor activities of CCI-779 in UBE2C overexpressed AR-positive CRPC.

Topics: Animals; Antineoplastic Agents; Cell Division; Cell Growth Processes; Cell Line, Tumor; Cyclin D1; Down-Regulation; Enzyme Inhibitors; G2 Phase; Humans; Male; Mice; Mice, Inbred BALB C; Orchiectomy; Prostatic Neoplasms; RNA, Messenger; Sirolimus; Transcription, Genetic; Transfection; Ubiquitin-Conjugating Enzymes; Xenograft Model Antitumor Assays

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Humans; Lapatinib; Molecular Targeted Therapy; Quinazolines; Sirolimus; Trastuzumab

Temsirolimus inhibits the mammalian target of rapamycin with demonstrated efficacy in patients with advanced renal cell cancer.. We present a retrospective analysis of our single-center experience with temsirolimus in patients pretreated with sunitinib, sorafenib or everolimus. Sixteen patients were treated within our center starting in December 2006 until September 2009. The majority of patients (14 of 16) had received a prior antiangiogenic pretreatment. We further analyzed the efficacy of subsequent treatment with temsirolimus in these patients.. Stable disease could be achieved in 8 of 14 pretreated patients (57%). The duration of median progression-free survival was 10 weeks (range 1-43). Especially patients with a good response to previous antiangiogenic treatment, a good overall condition and a low Memorial Sloan Kettering Cancer Center (MSKCC) score benefited from subsequent treatment with temsirolimus. We did not see any complete or partial response meeting the World Health Organization criteria. Temsirolimus was well tolerated.. Temsirolimus appears to be an effective and well-tolerated substance in the treatment of patients with a good performance status, low MSKCC score and stable disease under previous antiangiogenic treatment in advanced renal cell cancer. However, its use is highly questionable in pretreated patients with a poor performance score and a high MSKCC score.

Topics: Aged; Aged, 80 and over; Anemia; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Diarrhea; Disease-Free Survival; Everolimus; Female; Humans; Indoles; Karnofsky Performance Status; Kidney Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Nausea; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Thrombocytopenia

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors; Recurrence; Sirolimus

Relapse after initial first-line chemotherapy shows a poor prognosis in metastatic urothelial cancer. Currently, several chemotherapeutic agents and targeted drugs are under evaluation for platin-resistant advanced urothelial carcinoma. Vinflunine has been approved for second-line treatment in this indication. We present a patient with initial T4 advanced and subsequently metastasized bladder cancer, who has shown prolonged survival of 44 months after radical cystectomy. During her clinical course, the patient received two different platinum-containing therapies, temsirolimus within a phase II protocol and subsequent vinflunine chemotherapy. Treatment duration was 15 weeks with temsirolimus and 9 weeks with vinflunine, respectively, with a stable disease period of 3.8 months under temsirolimus therapy. This case is an example of how patients can derive a survival benefit from adequate sequencing of surgery and medical treatment including the newest therapies, even in advanced disease.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Female; Humans; Middle Aged; Sirolimus; Time Factors; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms; Vinblastine

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Humans; Interferon-alpha; Neoplasm Metastasis; Sirolimus

Topics: Adult; Aged; Antibiotics, Antineoplastic; Everolimus; Female; Granuloma, Pyogenic; Humans; Male; Middle Aged; Paronychia; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Deep infiltrating endometriosis (DIE) is a particular clinical and histological entity of endometriosis responsible for chronic pelvic pain and infertility. Here we characterize the proliferative phenotype of DIE cells, to explore the cellular and molecular mechanisms that could explain their aggressive potential. In addition, the inhibition of mTOR/AKT pathway was tested, as a potential treatment of DIE. Included were 22 patients with DIE and 12 control patients without endometriosis. Epithelial and stromal cells were extracted from biopsies of eutopic endometrium and deep infiltrating endometriotic nodules from patients with DIE. Cell proliferation was determined by thymidine incorporation. Oxidative stress was assayed by spectrofluorometry. The ERK and mTOR/AKT pathways were analyzed in vitro by Western blot and for AKT in vivo in a mouse model of DIE. The proliferation rate of eutopic endometrial cells and of deep infiltrating endometriotic cells from DIE patients was higher than that of endometrial cells from controls. The hyperproliferative phenotype of endometriotic cells was associated with an increase in endogenous oxidative stress, and with activation of the ERK and mTOR/AKT pathways. mTOR/AKT inhibition by temsirolimus decreased endometriotic cell proliferation both in vitro and in vivo in a mouse model of DIE. Blocking the mTOR/AKT pathway offers new prospects for the treatment of DIE.

Topics: Adult; Animals; Biopsy; Cell Proliferation; Disease Models, Animal; Endometriosis; Endometrium; Female; Humans; Mice; Mice, Nude; Middle Aged; Oxidative Stress; Phenotype; Protein Kinase Inhibitors; Reactive Oxygen Species; Sirolimus; Spectrometry, Fluorescence; TOR Serine-Threonine Kinases

With the introduction of targeted drug therapies, a paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards to replace the use of cytokines as standard therapy. Recently, these substances have been complemented by everolimus and pazopanib. An interdisciplinary consensus conference was held to discuss which criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2009 conference provided the basis for the 2010 meeting. The results of the 2010 conference are presented as short theses.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Cooperative Behavior; Cytokines; Disease Progression; Everolimus; Evidence-Based Medicine; Humans; Indazoles; Indoles; Interdisciplinary Communication; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Patient Care Team; Phenylurea Compounds; Platelet-Derived Growth Factor; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Signal Transduction; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The present study was performed to investigate the possible role of mTOR inhibitors in restoring chemosensitivity to adriamycin/cisplatin and elucidate the underlying mechanism. Combining adriamycin/cisplatin with torisel synergistically inhibited the cell proliferation in human oropharyngeal carcinoma cell line KB and its multidrug-resistant subclone KB/7D. Combining adriamycin and torisel inhibited the phosphorylation of 4EBP-1 and p70S6K, the proteins involved in mTOR pathway, increased expression of γH2AX indicative of DNA damage, triggered cell cycle arrest at G2/M and apoptosis. We conclude that chromatin decondensation by DNA damage provided an easy access for torisel to block the translation of proteins essential for DNA repair thereby restoring the chemosensitivity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cisplatin; DNA Damage; DNA Repair; DNA Topoisomerases, Type II; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Eukaryotic Initiation Factors; Everolimus; Female; Head and Neck Neoplasms; Humans; Phosphorylation; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Topoisomerase II Inhibitors; TOR Serine-Threonine Kinases

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Cetuximab; Colonic Neoplasms; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Eruptions; ErbB Receptors; Erlotinib Hydrochloride; Everolimus; Facial Dermatoses; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib; Trastuzumab

Inhibition of the mTOR signaling pathway promotes initiation of autophagy. However, recent studies indicate that autophagy is a self-defense mechanism of cancer cells that are subjected to anti-tumor agents and that blocking autophagy can trigger apoptosis. Here, we examined the effects of an mTOR inhibitor, temsirolimus, on a malignant fibrous histiocytoma (MFH) cell line, Nara-H cells, and the effect of suppressing autophagy on the induction of apoptosis in these MFH cells. In Nara-H cells, we examined the effects of temsirolimus treatment on cell proliferation using the CellTiter 96® AQueous One Solution Cell Proliferation Assay and on phosphorylation of mTOR pathway components and autophagy using Western blot-based assays. Furthermore, we examined the effects of temsirolimus with or without 3-methyladenine (3-MA) on induction of apoptosis using fluorescent microscopic analysis. In Nara-H cells, temsirolimus treatment inhibited cell proliferation, suppressed phosphorylation of mTOR pathway components, and induced autophagy as assessed by LC-3 II expression. Moreover, treatment with a combination of temsirolimus and 3-MA induced apoptosis in Nara-H cells. Apparently, simultaneous inhibition of autophagy and mTOR induced apoptosis in Nara-H cells because inhibition of autophagy prevented the cells from protecting themselves from the effects of the inhibition of mTOR. Therefore, a combination therapy that includes an mTOR inhibitor and an autophagy inhibitor (temsirolimus and 3-MA, respectively) may effectively treat MFH by inducing apoptosis in tumor cells.

Topics: Apoptosis; Autophagy; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Histiocytoma, Malignant Fibrous; Humans; Microscopy, Fluorescence; Oncogene Protein v-akt; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Staining and Labeling; TOR Serine-Threonine Kinases

Two acrylic hydrogels, of low cross-linking content and carrying the L-valine residues, were synthesized and studied as a platform to load and release the chemotherapeutic agent cisplatin. The platinum(II)-complex species showed a well-defined stoichiometric ratio in which two carboxylate groups of the collapsing gel coordinate a metal center; this was confirmed by FT-IR spectra. When loaded in water, a zero-order release rate of platinum(II)-species was shown in the physiologic solution (PBS, pH 7.40) for more than one week. Moreover, the amount of platinum(II)-species released from the hydrogel may be improved either by the cross-linking degree and by the temperature. Any increase of the cross-links results in a decreased slope of the straightline Pt(II)/gel (mg/g) versus time, whereas the increasing temperature results in a greater amount of platinum(II)-species in solution. The chemical- and swelling-controlled release are the main mechanisms supervising the whole release process. On the other hand, the loading of cisplatin and temsirolimus in DMF showed a characteristic two phase releasing pattern; the initial burst effect was always followed by the zero-order release rate for a week. In this case only a swelling-controlled mechanism was mainly invoked. The cytotoxic activity towards Me665/2/21 human melanoma cell line, afforded by the cisplatin-loaded hydrogel, was close and in some cases higher compared to the native cisplatin at the same concentration; an interesting synergy in term of cytotoxicity was observed when a combined treatment of temsirolimus and cisplatin was used, although temsirolimus exerted only a moderate inhibition of cell proliferation.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cisplatin; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Hydrogen-Ion Concentration; Sirolimus; Temperature; Valine

The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administered in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p < 0.05, and 26 ± 17% from 11 to 13 weeks, p < 0.01), compared with 493 ± 160 and 376 ± 50% increases, respectively, in vehicle-treated groups. Temsirolimus reduced tumor vascular density, 36 to 48 and 58 to 60%, p < 0.05, by the Texas red-dextran method or CD31-positive vessel count, respectively. Temsirolimus reduced tumor macrophage burden by 46% at 13 weeks (p < 0.05). Temsirolimus inhibited (p < 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors.

Topics: Animals; Biomarkers, Pharmacological; Cell Line, Tumor; Disease Progression; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Infusions, Intravenous; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Translational Research, Biomedical; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Aged; Humans; Male; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Salivary Ducts; Salivary Gland Neoplasms; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

An extremely rare adult example of renal carcinoma with t(6;11)(p21;q12 or q13) is presented here. The tumor of a 45-year-old Japanese male, excised under the diagnosis of renal cell carcinoma, was a well circumscribed 7 cm mass with light brown sectioned surfaces. Histologically, it was composed of a major population of large polygonal epithelioid cells in a nested alveolar growth and a subpopulation of smaller cells clustering around hyaline basement membrane material. The former cells possessed ample, clear to eosinophilic granular cytoplasm with well-defined cell borders and the latter was frequently accompanied by psammomatous calcification. These tumor cells exhibited immunoreactivity for melanoma markers, transcription factor EB and cathepsin K, but were not reactive for epithelial markers and transcription factor E3. While pulmonary metastatic foci that were noted preoperatively progressed rapidly following interferon-based therapy, subsequent sunitinib malate yielded a partial response and stabilized the lung metastasis for 6 months after surgery. We could trace 20 cases of 6p21 translocation renal carcinoma, among which only four were in individuals older than 40 years. Description of a new case like this is important since little is known about the prognosis and treatment of adult patients with this condition.

Topics: Antineoplastic Combined Chemotherapy Protocols; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biomarkers, Tumor; Carcinoma, Renal Cell; Cathepsin K; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 6; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Indoles; Interferons; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Pyrroles; Sirolimus; Sunitinib; Translocation, Genetic

The management of neuropathic pain is unsatisfactory, and new treatments are required. Because the sensitivity of a subset of fast-conducting primary afferent nociceptors is thought to be regulated by the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, selectively targeting mTORC1 represents a new strategy for the control of chronic pain. Here we show that activated mTOR was expressed largely in myelinated sensory fibers in mouse and that inhibiting the mTORC1 pathway systemically alleviated mechanical hypersensitivity in mouse models of inflammatory and neuropathic pain. Specifically, systemic administration of mTORC1 inhibitor temsirolimus (CCI-779), both acutely (25 mg/kg i.p.) and chronically (4 daily 25 mg/kg i.p.), inhibited the mTORC1 pathway in sensory axons and the spinal dorsal horn and reduced mechanical and cold hypersensitivity induced by nerve injury. Moreover, systemic treatment with CCI-779 also reduced mechanical but not heat hypersensitivity in an inflammatory pain state. This treatment did not influence nociceptive thresholds in naive or sham-treated control animals. Also, there was no evidence for neuronal toxicity after repeated systemic treatment with CCI-779. Additionally, we show that acute and chronic i.p. administration of Torin1 (20 mg/kg), a novel ATP-competitive inhibitor targeting both mTORC1 and mTORC2 pathways, reduced the response to mechanical and cold stimuli in neuropathic mice. Our findings emphasize the importance of the mTORC1 pathway as a regulator of nociceptor sensitivity and therefore as a potential target for therapeutic intervention, particularly in chronic pain.

Topics: Animals; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Neural Inhibition; Neuralgia; Nociceptors; Posterior Horn Cells; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Carcinoma; Carcinoma, Papillary; Carcinoma, Renal Cell; Dermatologic Agents; Fatal Outcome; Female; Humans; Hydrocortisone; Keratin-7; Kidney Neoplasms; Lymphatic Metastasis; Middle Aged; Paired Box Transcription Factors; PAX8 Transcription Factor; Sirolimus; Skin Neoplasms; Thyroid Cancer, Papillary; Thyroid Neoplasms

Dysregulation of the mammalian target of rapamycin (mTOR) signaling has been found in many human cancers, particularly those with loss of the tumor suppressor PTEN. However, mTORC1 inhibitors such as temsirolimus have only modest activity when used alone and may induce acquired resistance by activating upstream mTORC2 and Akt. Other tumors that do not depend upon PI3K/Akt/mTOR signaling for survival are primarily resistant. This study tested the hypothesis that the limited clinical efficacy of temsirolimus is due to a compensatory increase in survival signaling pathways downstream of Akt as well as an incomplete block of 4E-BP1-controlled proliferative processes downstream of mTOR. We explored the addition of a PI3K inhibitor to temsirolimus and identified the mechanism of combinatorial synergy. Proliferation assays revealed that BEZ235 (dual PI3K/mTOR inhibitor) or ZSTK474 (pan PI3K inhibitor) combined with temsirolimus synergistically inhibited cell growth compared to cells treated with any of the agents alone. Co-treatment resulted in G0/G1 cell cycle arrest and up-regulation of p27. Cell death occurred through massive autophagy and subsequent apoptosis. While molecular profiling revealed that, in most cases, sensitivity to temsirolimus alone was most marked in cells with high basal phospho-Akt resulting from PTEN inactivation, combining a PI3K inhibitor with temsirolimus prevented compensatory Akt phosphorylation and synergistically enhanced cell death regardless of PTEN status. Another molecular correlate of synergy was the finding that temsirolimus treatment alone blocks downstream S6 kinase signaling, but not 4E-BP1. Adding BEZ235 completely abrogated 4E-BP1 phosphorylation. We conclude that the addition of a PI3K inhibitor overcomes cellular resistance to mTORC1 inhibitors regardless of PTEN status, and thus substantially expands the molecular phenotype of tumors likely to respond.

Topics: Blotting, Western; Cell Cycle; Cell Division; Cell Line, Tumor; Drug Synergism; Humans; Imidazoles; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Quinolines; Sirolimus; TOR Serine-Threonine Kinases; Triazines

Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multi-targeting approach against PI3K, mTORC1/2 and MAPK.

Topics: Adaptor Proteins, Signal Transducing; Apoptosis; Carcinoma, Transitional Cell; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Enzyme Activation; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphoproteins; Proto-Oncogene Proteins c-akt; Quinolines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Urinary Bladder Neoplasms

Hormonal dependence of breast cancer has been known for a long time, yet about half of breast cancers with estrogen receptor will not respond to antihormonal therapy. Now, we know that this resistance may be related to a dysfunction of the estrogen pathway, or that of growth factors and particularly the pathway of cell activation PI3K/Akt/mTOR. Prevention of these different mechanisms of resistance could involve combination therapies such as anti-estrogens (SERMs, aromatase inhibitors) with inhibitors of the activity of growth factors that are particularly temsirolimus and everolimus for the activation pathway cell PI3K/Akt/mTOR.

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases

Targeted agents sunitinib and temsirolimus are effective in advanced renal cell carcinoma. Treatment algorithms for single-agent use have been proposed in order to optimize timing and type of therapy. The aim of this study was to investigate the tolerability and adverse event profile of patients who received sunitinib and temsirolimus in sequence. We performed a retrospective analysis of patients with advanced renal cell carcinoma who received temsirolimus after disease progression under sunitinib therapy. Dosages of both drugs were in accordance with the recommendations given by the respective manufacturers. Temsirolimus was provided before its official approval within a compassionate use program. Adverse event assessment followed the National Cancer Institute Common Toxicity Criteria. Thirteen patients receiving temsirolimus after progression under sunitinib were identified. Overall treatment time with targeted drugs (sunitinib/temsirolimus) was 34.8 (17-78) weeks, treatment with sunitinib was 28.6 (12-72), and with temsirolimus 6.2 (2-16) weeks, respectively, whereas mean therapy interruption time between both approaches was 4.4 (2-12) weeks. Under sunitinib, we observed 52 transient adverse events, 49 (94.2%) were of grade I/II, whereas 3 (5.8%) were of grade III. Under temsirolimus 36 adverse events, only grade I/II in nature were remarked. Sequential use of temsirolimus after progression under sunitinib seems to be feasible and results in a predictable, medically manageable side effect profile. Further evaluation is necessary to define the oncological validity of this sequencing approach.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Compassionate Use Trials; Feasibility Studies; Female; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Pyrroles; Retrospective Studies; Sirolimus; Sunitinib

Spontaneous pyopneumothorax is a very rare occurrence, even in cancer treated patients. Here we present two consecutive cases of spontaneous pyopneumothorax that occurred early after initiation of mTOR inhibitors for the treatment of renal cell carcinoma with subpleural pulmonary metastasis. In these two cases, necrosis and excavation of lung metastasis were observed, suggesting their involvement in the pathogenic mechanism of pyopneumothorax. This report extends the available experience of the pulmonary side effects of these novel targeted therapies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Calcitonin; Carcinoma, Renal Cell; Combined Modality Therapy; Disease Susceptibility; Everolimus; Fatal Outcome; Female; Humans; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Necrosis; Neoplasm Proteins; Nephrectomy; Niacinamide; Phenylurea Compounds; Pneumonia, Bacterial; Pneumothorax; Protein Precursors; Pyridines; Pyrroles; Rupture, Spontaneous; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR), which phosphorylates p70S6K and 4EBP1 and activates the protein translation process, is upregulated in cancers and its activation may be involved in cancer development.. In this study, we investigated the tumour-suppressive effects of rapamycin and its new analogue CCI-779 on hepatocellular carcinoma (HCC).. Rapamycin and its new analogue CCI-779 were applied to treat HCC cells. Cell proliferation, cell cycle profile and tumorigenicity were analysed.. In human HCCs, we observed frequent (67%, 37/55) overexpression of mTOR transcripts using real-time reverse transcriptase-polymerase chain reaction. Upon drug treatment, PLC/PRF/5 showed the greatest reduction in cell proliferation using the colony formation assay, as compared with HepG2, Hep3B and HLE. Rapamycin was a more potent antiproliferative agent than CCI-779 in HCC cell lines. Proliferation assays by cell counting showed that the IC(50) value of rapamycin was lower than that of CCI-779 in PLC/PRF/5 cells. Furthermore, flow cytometric analysis showed that both drugs could arrest HCC cells in the G(1) phase but did not induce apoptosis of these cells, suggesting that these mTOR inhibitors are cytostatic rather than cytotoxic. Upon rapamycin and CCI-779 treatment, the phosphorylation level of mTOR and p70S6K in HCC cell lines was significantly reduced, indicating that both drugs can suppress mTOR activity in HCC cells. In addition, both drugs significantly inhibited the growth of xenografts of PLC/PRF/5 cells in nude mice.. Our findings indicate that rapamycin and its clinical analogue CCI-779 possess tumour-suppressive functions towards HCC cells.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Cell Count; Cell Line, Transformed; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antihypertensive Agents; Antineoplastic Agents; Aortic Aneurysm; Aortic Dissection; Carcinoma, Renal Cell; Combined Modality Therapy; Humans; Hypertension; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Nephrectomy; Pyrroles; Sirolimus; Sunitinib

Until recently, the standard therapy for metastatic renal cell carcinoma (mRCC) in Germany consisted of interleukin-2 (IL-2), interferon-alfa (IFN) as single agents or in combination, with or without chemotherapy. Since 2005, new drugs (target drugs) in the therapy for mRCC are available. The aim of this study was to analyse the current therapy standard in Germany.. By representative telephone interviews (GFK-Nürnberg by order of DGFIT) the following colleagues were contacted A: urologists in private practice (n = 40), B: oncologists in private practice (n = 40), C: hospital urologists (n = 35) and D: hospital oncologists (n = 35). Screening criteria were 1) responsibility for therapy in mRCC; 2) therapy of at least 10 patients with mRCC per year.. Patients/year: A: n = 19, B: n = 17, C: n = 43, D: n = 21. 98% of patients with mRCC were treated: A: the most frequent therapy was sunitinib (43%, 42%, 33% as first-, second-, third-line), B: the most frequent therapy was sunitinib (45% as first-line, 37% as second-line), the most frequent third-line therapy was sorafenib (35%); C: the most frequent therapy were sorafenib and sunitinib (first-line 26% vs. 27%, second-line 46% vs. 42%), in third-line therapy additionally temsirolimus 24%; D: primary sorafenib and sunitinib (first-line 33% vs. 40%, second-line 46% vs. 42%), in third-line therapy additionally temsirolimus 23%. Immunotherapy (IL-2, IFN with or without chemotherapy) in mRCC plays in Germany for the second- and third-line therapy in A-D no major role (less than 10%). Otherwise, for first-line therapy immunotherapy has some relevance: A: 25%, B: 37%, C: 33%, D: 16%. The most important criteria for therapy decision making in A-D were: efficacy, toxicity, drug approval status.. Most patients with mRCC in Germany were seen by hospital urologists. Sunitinib (in first-line) and sorafenib (in second-line) are currently the most frequent prescribed drugs in mRCC. Temsirolimus is used mostly for third-line therapy (followed by sunitinib/sorafenib). Treatment of mRCC in Germany is increasingly being performed by oncologists.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Attitude of Health Personnel; Benzenesulfonates; Carcinoma, Renal Cell; Cooperative Behavior; Data Collection; Drug Delivery Systems; Drug Utilization; Germany; Humans; Immunotherapy; Indoles; Interdisciplinary Communication; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Medical Oncology; Niacinamide; Patient Care Team; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Urology

Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor performance in a transgenic mouse model of spinocerebellar ataxia type 3. Temsirolimus inhibits mammalian target of rapamycin and hence upregulates protein degradation by autophagy. Temsirolimus reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. Temsirolimus is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of spinocerebellar ataxia type 3. Using this disease model and treatment paradigm, we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of spinocerebellar ataxia type 3. This identified ubiquitin specific peptidase-15, which showed expression changes at both the messenger ribonucleic acid and protein level. Ubiquitin specific peptidase-15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalized following temsirolimus treatment. In this mouse model with relatively mild disease progression, the number of transcripts changed was low and the magnitude of these changes was small. However, the importance of these transcriptional alterations in the pathogenesis of spinocerebellar ataxia type 3 remains unclear.

Topics: Animals; Ataxin-3; Autophagy; Cells, Cultured; Disease Models, Animal; Humans; Machado-Joseph Disease; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nuclear Proteins; Rats; Rats, Sprague-Dawley; Sirolimus; Transcription Factors

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has exhibited promising anticancer activity for the treatment of renal cell cancers (RCC). Survivin expression has been implicated in drug resistance and reducing its levels with the histone deacetylase (HDAC) inhibitor vorinostat may enhance the anticancer activity of temsirolimus.. The sensitivity of RCC cell lines to the combination of temsirolimus and vorinostat was determined by measuring cell viability, clonogenic survival, and apoptosis. The effects of this combination on survivin levels were determined in vitro and in vivo. Survivin expression was silenced using small interfering RNA to evaluate its role in determining sensitivity to temsirolimus and vorinostat. The effect of the combination on angiogenesis was also determined in RCC xenograft models.. Vorinostat synergistically improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in two xenograft models in vivo. While each single agent led to a modest decrease in survivin levels, the combination dramatically reduced its expression, which correlated with an induction of apoptosis. Silencing survivin levels induced apoptosis and significantly improved the efficacy of temsirolimus and vorinostat. In addition, the temsirolimus/vorinostat combination led to a strong reduction in angiogenesis.. Vorinostat augmented the anticancer activity of temsirolimus in both in vitro and in vivo models of RCC. The effectiveness of the combination was due to a decrease in survivin levels and corresponding induction of apoptosis, and enhanced inhibition of angiogenesis. Targeting survivin may be a promising therapeutic strategy to improve RCC therapy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Synergism; Humans; Hydroxamic Acids; Inhibitor of Apoptosis Proteins; Kidney Neoplasms; Mice; Mice, Nude; Microtubule-Associated Proteins; Repressor Proteins; Sirolimus; Survivin; Vorinostat; Xenograft Model Antitumor Assays

Activation of the beta-catenin and receptor kinase pathways occurs often in medulloblastoma, the most common pediatric malignant brain tumor. In this study, we show that molecular cross-talk between the beta-catenin and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways is crucial to sustain medulloblastoma pathophysiology. Constitutive activation of phosphoinositide-dependent protein kinase 1 (PDK1), Akt, and phosphorylation of [corrected] glycogen synthase kinase 3beta (GSK-3beta) was detected by immunohistochemistry in all primary medulloblastomas examined (n = 41). Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected beta-catenin signaling by activation [corrected] of GSK-3beta, [corrected] resulting in cytoplasmic retention of beta-catenin and reduced expression of its target genes cyclin D1 and c-Myc. The PDK1 inhibitor OSU03012 induced mitochondrial-dependent apoptosis of medulloblastoma cells and enhanced the cytotoxic effects of chemotherapeutic drugs in a synergistic or additive manner. In vivo, OSU03012 inhibited the growth of established medulloblastoma xenograft tumors in a dose-dependent manner and augmented the antitumor effects of mammalian target of rapamycin inhibitor CCI-779. These findings demonstrate the importance of cross-talk between the PI3K/Akt and beta-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease.

Topics: Animals; Antineoplastic Agents; beta Catenin; Cerebellar Neoplasms; Flow Cytometry; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Medulloblastoma; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor Cross-Talk; RNA, Small Interfering; Signal Transduction; Sirolimus; Transfection; Wnt Proteins; Xenograft Model Antitumor Assays

Topics: Aged; Angiomyolipoma; Antineoplastic Agents; Embolization, Therapeutic; Epithelioid Cells; Erythrocyte Transfusion; Hepatectomy; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Magnetic Resonance Imaging; Male; Nephrectomy; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

The mammalian target of rapamycin (mTOR) is a major component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway that is dysregulated in 50% of all human malignancies. Rapamycin and its analogues (rapalogs) partially inhibit mTOR through allosteric binding to mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report WYE-125132 (WYE-132), a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC(50): 0.19 +/- 0.07 nmol/L; >5,000-fold selective versus PI3Ks). WYE-132 inhibited mTORC1 and mTORC2 in diverse cancer models in vitro and in vivo. Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT(S473) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT(T308), highlighting a prominent and direct regulation of AKT by mTORC2 in cancer cells. Compared with the rapalog temsirolimus/CCI-779, WYE-132 elicited a substantially stronger inhibition of cancer cell growth and survival, protein synthesis, cell size, bioenergetic metabolism, and adaptation to hypoxia. Oral administration of WYE-132 to tumor-bearing mice showed potent single-agent antitumor activity against MDA361 breast, U87MG glioma, A549 and H1975 lung, as well as A498 and 786-O renal tumors. An optimal dose of WYE-132 achieved a substantial regression of MDA361 and A549 large tumors and caused complete regression of A498 large tumors when coadministered with bevacizumab. Our results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy.

Topics: Animals; Apoptosis; Cell Cycle; Cell Growth Processes; Cell Hypoxia; Female; Humans; Intracellular Signaling Peptides and Proteins; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Neoplasms; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Pyrazoles; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

The role of autophagy in the degradation of aggregate-prone proteins has been well established. As a result, autophagy upregulation has become an attractive therapeutic strategy for the treatment of proteinopathies, a group of diseases caused by the accumulation of mutant misfolded proteins. We have previously shown that rapamycin attenuates the phenotype in a mouse model of Huntington disease when administered pre-symptomatically and have recently extended this to demonstrate the effectiveness of rapamycin in a transgenic mouse model of spinocerebellar ataxia type 3, a polyglutamine disorder caused by mutations in the ataxin-3 gene. Rapamycin, administered from the initial onset of disease signs, improves motor coordination and results in a decrease in the levels of soluble mutant ataxin-3 and protein aggregates in the brain.

Topics: Animals; Antineoplastic Agents; Ataxin-3; Humans; Huntington Disease; Machado-Joseph Disease; Mice; Nerve Tissue Proteins; Nuclear Proteins; Repressor Proteins; Sirolimus

Targeted therapies have fundamentally altered the therapy of metastatic renal cell carcinoma (mRCC). Sunitinib today is an internationally recommended reference standard in first-line therapy; other drugs such as Temsirolimus, Everolimus, Bevacizumab (in combination with Interferon-alpha) and Sorafenib are part of the therapeutic arsenal. Practitioners thus have now more and better therapeutic options at hand, leading to a significantly improved prognosis for mRCC patients. Numerous ongoing research activities aim at the improvement of the benefits of the new compounds in the metastatic situation or application earlier in the course of the disease. Key aspects of future development in RCC are the optimization of the current therapy options by developing new targeted therapies, the search for the best combinations and sequences including the role of nephrectomy and the assessment in the adjuvant or neo-adjuvant setting. The following contribution provides an overview of ongoing studies, thus giving insight into the future therapy of RCC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Combined Modality Therapy; Drug Delivery Systems; Everolimus; Evidence-Based Medicine; Forecasting; Germany; Humans; Indoles; Kidney Neoplasms; Nephrectomy; Prognosis; Pyrroles; Sirolimus; Sunitinib

Topics: Female; Heart Neoplasms; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Perivascular Epithelioid Cell Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome; Uterine Neoplasms

Cutaneous metastasis is a rare form of presentation of renal cell carcinoma (RCC). Case reports and case series of RCC with skin metastasis in the English literature from 1972 to 2008 were identified by searching the keywords "renal cell cancer," "papillary renal cell tumor," "skin metastasis," and "cutaneous metastasis" in the National Library of Medicine, PUBMED, OVID, and EMBASE search engines. Although a few cases of RCC with skin metastasis are reported in the literature, almost all are clear cell histologic type. We are reporting a unique case of papillary RCC with cutaneous metastases diagnosed at our institution along with a comprehensive literature review of papillary RCC etiology, clinical presentation, prognosis, diagnosis, and the treatment options that are currently available.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Male; Middle Aged; Sirolimus; Skin Neoplasms

A 35-year-old woman presented with a 12-cm right renal mass with retroperitoneal lymph node involvement and pulmonary and bone metastases. Renal mass biopsy revealed an unclassified high-grade non-clear cell renal cell carcinoma (RCC) with eosinophilic cells. Due to the extent of the disease, neoadjuvant temsirolimus was initiated. After 6 wk of treatment, a significant downstaging of the disease and complete disappearance of the metastases were noticed on computed tomography scan. Three months later, a laparoscopic radical nephrectomy and lymphadenectomy was performed. Final pathology confirmed a high-grade non-clear cell RCC, with necrotic changes on lymph node specimens, pT1bN0Mx.

Topics: Adult; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Sirolimus

Advanced renal cell carcinoma is associated with a poor prognosis and is refractory to standard chemotherapy. Recent progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies. The management of metastatic RCC has been revolutionized with the development of targeted molecular therapies against VEGF-VEGFR and mTOR. Randomized phase III clinical trials demonstrated clinical benefit for patients with advanced RCC in overall survival and progression free survival. At the moment, six molecules have been approves in advanced RCC: cytokines (IL-2 and IFN), antiangiogenic therapies (sunitinib, sorafenib, bevacizumab) and mTOR inhibitors (Temsirolimus, everolimus). Nephrectomy is an important component of the multimodality treatment of mRCC. Prospective trials will be assessed the value of nephrectomy in patients treated by antiangiogenic therapies. Large randomized trial are ongoing to evaluate these new therapies in adjuvant setting.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Everolimus; Humans; Indoles; Interferons; Interleukin-2; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Metabolic Networks and Pathways; Nephrectomy; Niacinamide; Phenylurea Compounds; Protein Serine-Threonine Kinases; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The treatment of metastatic kidney cancer has dramatically changed in the last three years, with demonstration of efficacy of sunitinib, sorafenib, temsirolimus, bevacizumab combined with interferon and more recently everolimus. Although the international guidelines have recently been reviewed, some major questions are still open. Particularly, the best order of administration of these targeted therapies should be considered, since sequential schedule becomes usual with the availability of these new agents. At the same time, the tolerability and efficacy of the combination of the targeted therapies are under investigation in clinical trials. We report recent studies, mainly presented during the ASCO 2007 and 2008 congress. Furthermore, other studies are ongoing to answer other important questions, to optimize the treatment of this disease, such as the role of nephrectomy in case of synchronous metastatic disease, or the efficacy of the targeted therapies in different histological subtype than clear cell carcinoma, or in neoadjuvant and adjuvant settings.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Combined Modality Therapy; Cytokines; ErbB Receptors; Humans; Indoles; Interferon-alpha; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Nephrectomy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The recent development of antiangiogenic agents has revolutionized the management of renal cell carcinoma. In less than two-years, the French health authorities have approved the use of four drugs (sorafenib, sunitinib bevacizumab, temsirolimus) for the treatment of locally advanced or metastatic renal cell carcinoma. A fifth drug (everolimus) should be on the market some time. Clinicians have changed their practice and are faced with a number of new adverse events. The management of toxic effects is essential to ensure treatment compliance and patient quality of life. The present report describes in detail the adverse events associated with each therapeutic class and the management of side effects.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Digestive System; Heart; Humans; Hypothyroidism; Indoles; Kidney Neoplasms; Lung Injury; Mucous Membrane; Muscle Fatigue; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Advanced or metastatic renal carcinoma represents a frequent disease in oncologic practice. Few years ago, in immunotherapy era, treatments had quickly reached deadlock. New therapies targeting vascular endothelial growth factors and their receptors (VEGF-R), sorafenib, sunitinib and bevacizumab, and the mammalian target of rapamycin (mTOR), temsirolimus and everolimus, have modified these patients prognosis and their quality of life in a few years. Nevertheless, patients included in randomized trials presented severe inclusion criteria. Then in the daily practice, patients have distinctive characteristics which were not evaluated in large pivotal studies: poor performance status, older patients, renal dysfunction, cerebral metastases or non clear cell renal cancer. In published trials, a few data concerning these situations are reported, and these studies have often included small samples, were retrospective or not randomised. However compared to global population, tolerance have not been very different in geriatric patients, or patients with poor performance status, or with central neurological metastases, or with papillary and chromophobe sub-types. On the contrary progression free or overall survivals increases are more difficult to confirm. Also before starting treatment, ratio between potential benefit and possible toxicities have to be evaluated. In patients with renal insufficiency, VEGF receptor inhibitors seem to be cautiously initiated at reduced doses, and to be increased according to tolerance. Due to these poor proof levels, clinical trials are needed for these specific populations.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Brain Neoplasms; Carcinoma, Renal Cell; Everolimus; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Protein Serine-Threonine Kinases; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The protein kinase mammalian target of rapamycin (mTOR) regulates mRNA translation and is inhibited by rapamycin. Signaling pathways involving mTOR are implicated in physiological and pathophysiological processes. We determined the spinal effects of the rapamycin analogue cell cycle inhibitor (CCI)-779 on neuronal responses and behavioral hypersensitivity in a model of persistent neuropathic pain. We also assessed the anatomical distribution of spinal mTOR signaling pathways. Specifically, we ligated rat spinal nerves L5 and L6 to produce a model of neuropathic pain. After confirming neuropathy with behavioral testing, we obtained in vivo single-unit extracellular stimulus-evoked recordings from deep dorsal horn spinal neurons. We applied CCI-779 spinally in electrophysiological and behavioral studies and assessed its effects accordingly. We also used immunohistochemistry to probe for mTOR signaling pathways in dorsal root ganglia (DRG) and the spinal cord. We found that spinally administered CCI-779 rapidly attenuated calibrated mechanically but not thermally evoked neuronal responses and mechanically evoked behavioral responses. Immunohistochemistry showed presence of mTOR signaling pathways in nociceptive-specific C-fiber DRG and in neurons of inner lamina II of the spinal cord. We conclude that alterations in the activity of spinal mTOR signaling pathways are crucial to the full establishment of spinal neuronal plasticity and behavioral hypersensitivity associated with nerve injury.. This study is consistent with growing evidence implicating mTOR signaling pathways as important modulators of persistent pain, providing novel insights into the molecular mechanisms of pain maintenance and potential for novel approaches into treating chronic pain.

Topics: Animals; Behavior, Animal; Electrophysiology; Hyperalgesia; Immunohistochemistry; Male; Neuralgia; Neuronal Plasticity; Peripheral Nervous System Diseases; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; Spinal Cord; Spinal Nerves; TOR Serine-Threonine Kinases

Local modulation of vascular mammalian target of rapamycin (mTOR) signaling reduces smooth muscle cell (SMC) proliferation after endovascular interventions but may be associated with endothelial cell (EC) toxicity. The trilaminate vascular architecture juxtaposes ECs and SMCs to enable complex paracrine coregulation but shields SMCs from flow. We hypothesized that flow differentially affects mTOR signaling in ECs and SMCs and that SMCs regulate mTOR in ECs.. SMCs and/or ECs were exposed to coronary artery flow in a perfusion bioreactor. We demonstrated by flow cytometry, immunofluorescence, and immunoblotting that EC expression of phospho-S6 ribosomal protein (p-S6RP), a downstream target of mTOR, was doubled by flow. Conversely, S6RP in SMCs was growth factor but not flow responsive, and SMCs eliminated the flow sensitivity of ECs. Temsirolimus, a sirolimus analog, eliminated the effect of growth factor on SMCs and of flow on ECs, reducing p-S6RP below basal levels and inhibiting endothelial recovery. EC p-S6RP expression in stented porcine arteries confirmed our in vitro findings: Phosphorylation was greatest in ECs farthest from intact SMCs in metal stented arteries and altogether absent after sirolimus stent elution.. The mTOR pathway is activated in ECs in response to luminal flow. SMCs inhibit this flow-induced stimulation of endothelial mTOR pathway. Thus, we now define a novel external stimulus regulating phosphorylation of S6RP and another level of EC-SMC crosstalk. These interactions may explain the impact of local antiproliferative delivery that targets SMC proliferation and suggest that future stents integrate design influences on flow and drug effects on their molecular targets.

Topics: Animals; Aorta; Arteries; Cell Communication; Cells, Cultured; Coronary Vessels; Endothelial Cells; Endothelium, Vascular; Humans; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Protein Serine-Threonine Kinases; Regional Blood Flow; Ribosomal Protein S6; Signal Transduction; Sirolimus; Stents; Swine; Swine, Miniature; TOR Serine-Threonine Kinases; Transcription Factors

With the introduction of targeted therapies, a -paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. The use of cytokines as the long-standing standard therapy has declined. New compounds like sunitinib, -sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards. Since mid-2009, these substances have been complemented by everolimus. An interdisciplinary consensus conference was held to discuss what criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2008 conference provided the basis for the 2009 meeting. The results of the 2009 conference are presented as short theses.

Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease Progression; Drug Delivery Systems; Everolimus; Humans; Indoles; Kidney Neoplasms; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Rapamycin analogs temsirolimus and everolimus have been approved for the treatment of advanced renal cancer and are being tested in a wide spectrum of human tumors. However, objective response rates with rapalogs in clinical trials were modest and variable. Identification of biomarkers capable of predicting response to rapalogs is of increasing interest. We analyzed pairwise Pearson correlation coefficients (r) between rapalogs activity and gene expression profile for each NCI-60 cell line. p27 showed the highest positive correlation among 9,706 gene probes tested. At cellular levels, breast cancer MCF-7, T47D, and BT-474 cells, expressing high levels of p27, were sensitive to rapalogs, whereas the cells expressed low levels of p27, such as MDA-MB-231, MDA-MB-468, and MDA-MB-435 cells, exhibited resistance to rapalogs. Mechanistic study indicated that this correlation is likely determined by the basal level of p27 regardless of the phosphorylation or redistribution of p27 upon rapalogs treatment, which may provide a putative threshold to block G1/S transition. Consistently, down-regulation of p27 by siRNA conferred MCF-7 and BT-474 cells insensitive to rapalogs. Moreover, a significant positive correlation between p27 gene expression and rapamycin anti-tumor activity was also observed in mice bearing different human cancer cell xenografts. In conclusion, p27 expression level is positively correlated with the anticancer activity of rapalogs in vitro and in vivo. We propose p27 expression level may be also a candidate predictive biomarker for patient selection for rapalogs-based therapy, which requires clinical validation in a series of patients treated with rapalogs.

Topics: Animals; Biomarkers; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Female; Humans; Immunoprecipitation; Mice; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chemotherapy, Adjuvant; Clinical Trials, Phase I as Topic; Disease Progression; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Intracellular Signaling Peptides and Proteins; Middle Aged; Perivascular Epithelioid Cell Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazines; Retroperitoneal Neoplasms; Sirolimus; Topotecan; TOR Serine-Threonine Kinases; Treatment Failure

Topics: Antineoplastic Agents; Humans; Kidney Neoplasms; Sirolimus; Survival Analysis

We have recently reported the importance of spinal rapamycin-sensitive pathways in maintaining persistent pain-like states. A descending facilitatory drive mediated through spinal 5-HT3 receptors (5-HT3Rs) originating from superficial dorsal horn NK1-expressing neurons and that relays through the parabrachial nucleus and the rostroventral medial medulla to act on deep dorsal horn neurons is known be important in maintaining these pain-like states. To determine if spinal rapamycin-sensitive pathways are activated by a descending serotonergic drive, we investigated the effects of spinally administered rapamycin on responses of deep dorsal horn neurons that had been pre-treated with the selective 5-HT3R antagonist ondansetron. We also investigated the effects of spinally administered cell cycle inhibitor (CCI)-779 (a rapamycin ester analogue) on deep dorsal horn neurons from rats with carrageenan-induced inflammation of the hind paw. Unlike some other models of persistent pain, this model does not involve an altered 5-HT3R-mediated descending serotonergic drive. We found that the inhibitory effects of rapamycin were significantly reduced for neuronal responses to mechanical and thermal stimuli when the spinal cord was pre-treated with ondansetron. Furthermore, CCI-779 was found to be ineffective in attenuating spinal neuronal responses to peripheral stimuli in carrageenan-treated rats. Therefore, we conclude that 5-HT3R-mediated descending facilitation is one requirement for activation of rapamycin-sensitive pathways that contribute to persistent pain-like states.

Topics: Action Potentials; Afferent Pathways; Animals; Carrageenan; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Immunosuppressive Agents; Inflammation; Nerve Fibers; Neurons; Ondansetron; Protein Kinase Inhibitors; Rats; Serotonin Antagonists; Sirolimus; Spinal Cord; Temperature

Topics: Antineoplastic Agents; Cord Blood Stem Cell Transplantation; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Salvage Therapy; Sirolimus; Thrombocytopenia; Treatment Outcome

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive neoplasm that mostly occurs in young males. No curative treatment options currently exist for this type of tumor and long-term survival remains poor. In vitro rapamycin induces apoptotic death of JN-DSRCT-1 cells, a possible model for desmoplastic small round cell tumors in which the EWS gene is fused to the WT1 gene. We therefore demonstrate the prolonged activity of temsirolimus, an mTOR-inhibitor, in a patient with DSRCT.

Topics: Abdominal Neoplasms; Antineoplastic Agents; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK(+) from ALK(-) subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK(+) and ALK(-) ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK(+) ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK(-) ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK(+) and not in ALK(-) cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Base Sequence; Cell Line, Tumor; Cell Proliferation; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Lymphoma, Large-Cell, Anaplastic; Mice; Mice, Transgenic; MicroRNAs; Multigene Family; Protein-Tyrosine Kinases; Receptor Protein-Tyrosine Kinases; Sirolimus; Xenograft Model Antitumor Assays

Mantle cell lymphoma (MCL) is a rare and aggressive type of B-cell non-Hodgkin's lymphoma. Patients become progressively refractory to conventional chemotherapy, and their prognosis is poor. However, a 38% remission rate has been recently reported in refractory MCL treated with temsirolimus, a mTOR inhibitor.Here we had the opportunity to study a case of refractory MCL who had tumor regression two months after temsirolimus treatment, and a progression-free survival of 10 months. In this case, lymph node biopsies were performed before and six months after temsirolimus therapy. Comparison of the two biopsies showed that temsirolimus inhibited tumor cell proliferation through cell cycle arrest, but did not induce any change in the number of apoptotic tumor cells. Apart from this cytostatic effect, temsirolimus had an antiangiogenic effect with decrease of tumor microvessel density and of VEGF expression. Moreover, numerous patchy, well-limited fibrotic areas, compatible with post-necrotic tissue repair, were found after 6-month temsirolimus therapy. Thus, temsirolimus reduced tumor burden through associated cytostatic and anti-angiogenic effects.This dual effect of temsirolimus on tumor tissue could contribute to its recently reported efficiency in refractory MCL resistant to conventional chemotherapy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Sirolimus; TOR Serine-Threonine Kinases

Delayed-type hypersensitivity (DTH) is classically defined as inflammation involving activated Th1 cells and cytokine production. DTH paw swelling, along with the cytokines IL-2, IFNγ, MCP-1 and TNFα, were inhibited in Balb/c mice by cyclosporine A (CsA). Surprisingly, the DTH response in the B6D2F1 mice was unaffected by CsA, despite a decrease in TNFα and IFNγ levels. IL-2 levels, however, were not decreased. To determine if the IL-2 production in the B6D2F1 strain is occurring through CD28-mediated costimulation, both CsA and CTLA-4Ig were administered. Paw swelling and IL-2 levels were decreased, indicating a role for costimulation. Co-administration of temsirolimus and CsA also reduced DTH and IL-2 levels in B6D2F1 mice, demonstrating involvement of the mTORC1 pathway. These results indicate that the cell activation pathways responsible for DTH differ with mouse strain. It is important to understand these differences in order to accurately interpret the results using potential therapeutic agents.

Topics: Abatacept; Animals; Antibodies; Autoimmunity; CD28 Antigens; Cell Movement; Cyclosporine; Cytokines; Erythrocytes; Female; Foot; Hypersensitivity, Delayed; Immunity, Cellular; Immunoconjugates; Interleukin-17; Interleukin-2; Lymph Nodes; Lymphocyte Activation; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Multiprotein Complexes; NFATC Transcription Factors; Protein Kinase Inhibitors; Proteins; Sheep; Signal Transduction; Sirolimus; Species Specificity; T-Lymphocytes; TOR Serine-Threonine Kinases; Vaccination

The mammalian target of rapamycin (mTOR) is engaged in the molecular pathogenesis of oral squamous cell carcinoma, which frequently invades the maxilla or the mandible. However, the effects of a mTOR inhibitor on bone destruction associated with oral squamous cell carcinoma are still unclear. In this study, we investigated the antitumor effect of temsirolimus-mediated mTOR inhibition against advanced oral squamous cell carcinoma. Temsirolimus inhibited the proliferation and migration of HSC-2 oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. Significantly, we clearly show that temsirolimus inhibited osteoclast formation both in vitro and in vivo. Reverse transcriptase-PCR analysis showed that temsirolimus decreased the mRNA expression of receptor activator for nuclear factor-κB ligand, known as an osteoclast differentiation factor in bone stromal ST2 cells. Moreover, temsirolimus normalized blood-free calcium concentration in mouse models for humoral hypercalcemia. These findings suggest that mTOR signaling is a potential target of oral squamous cell carcinoma associated with bone destruction, and hence we describe the efficacy of temsirolimus for the treatment of advanced oral squamous carcinoma.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Bone Resorption; Carcinoma, Squamous Cell; Cell Movement; Cells, Cultured; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Osteoclasts; Sirolimus; Xenograft Model Antitumor Assays

Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined.. To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective.. One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib-everolimus or temsirolimus-sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment.. PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS).. Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3-6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6-10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data.. Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Feasibility Studies; Female; Humans; Indoles; Italy; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome

We have previously shown that the plant-derived compound parthenolide (PTL) can impair the survival and leukemogenic activity of primary human acute myeloid leukemia (AML) stem cells. However, despite the activity of this agent, PTL also induces cellular protective responses that likely function to reduce its overall cytotoxicity. Thus, we sought to identify pharmacologic agents that enhance the antileukemic potential of PTL. Toward this goal, we used the gene expression signature of PTL to identify compounds that inhibit cytoprotective responses by performing chemical genomic screening of the Connectivity Map database. This screen identified compounds acting along the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways. Compared with single agent treatment, exposure of AML cells to the combination of PTL and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors significantly decreased viability of AML cells and reduced tumor burden in vitro and in murine xenotransplantation models. Taken together, our data show that rational drug combinations can be identified using chemical genomic screening strategies and that inhibition of cytoprotective functions can enhance the eradication of primary human AML cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers, Tumor; Blotting, Western; Bone Marrow; Cell Proliferation; Cells, Cultured; Drug Synergism; Enzyme Inhibitors; Flow Cytometry; Gene Expression Profiling; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, SCID; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sesquiterpenes; Sirolimus; TOR Serine-Threonine Kinases

Several years ago, the oncologist was limited to a narrow scope of immunotherapeutic agents for the treatment of metastatic renal cell carcinoma (mRCC). Within the past 5 years, however, a total of 6 targeted agents have been approved for the treatment of this disease. The abundance of novel therapies has introduced a new dilemma for the oncologist--namely, how can one make evidence-based choices amongst available agents? Recently, two Phase III studies (AVOREN and Cancer and Leukemia Group B [CALGB] 90206) assessed the activity of 1st-line therapy with bevacizumab in combination with interferon-alfa (IFN-alfa) as compared to IFN-alfa alone. Both trials demonstrated a significant benefit in progression-free survival (PFS) with bevacizumab, with no benefit in overall survival (OS). Herein, the implications of these data are assessed in the context of data reported from other recent pivotal trials in mRCC. Methods to resolve areas of clinical equipoise in the treatment of mRCC (i.e., comparative trial designs and biomarker analyses) are also proposed.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Multicenter Studies as Topic; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis

Until recently, immunotherapy has been the standard of care for patients with nonresectable metastatic renal cell carcinoma (mRCC); however, immunotherapy is associated with a low response rate and significant toxicity. Because of their demonstrated ability to prolong progression-free survival, agents targeting vascular endothelial growth factor receptors or the mammalian target of rapamycin now have become standard therapies for patients with mRCC. Attaining lasting clinical benefits, however, requires multiple lines of therapy. This case study reports the case of a 52-year-old man with mRCC who remained free of disease progression for 48 months while receiving sequential therapy of sunitinib, everolimus, sorafenib, and temsirolimus.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Everolimus; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Kidney Neoplasms; Randomized Controlled Trials as Topic; Sirolimus

We examined the therapeutic potential of a novel MEK inhibitor, RDEA119, and its synergism with the mTOR inhibitor, temsirolimus, in thyroid cancer cell lines. RDEA119 potently inhibited the proliferation of the 4 cell lines that harbored BRAF mutation but had no or modest effects on the other 4 cells that harbored wild-type BRAF (IC(50) of 0.034-0.217 μM vs. 1.413-34.120 μM). This inhibitory effect of RDEA119 in selected cell lines OCUT1 (BRAF V600E(+), PIK3CA H1047R(+)) and SW1376 (BRAF V600E(+)) was enhanced by combination with the mTOR inhibitor, temsirolimus. The PTEN-deficient cell FTC133 was highly sensitive to temsirolimus but insensitive to RDEA119, and simultaneous treatment with the latter enhanced the sensitivity of the cell to the former. The KAT18 (wild-type) cell was not sensitive to either drug alone but became sensitive to the combination of the 2 drugs. The drug synergy was confirmed by combination index and isobologram analyses. RDEA119 and temsirolimus also showed synergistic effects on autophagic death of OCUT1 and KAT18 cells selectively tested. Dramatic synergistic effects of the 2 drugs were also seen on the growth of FTC133 xenograft tumors in nude mice. Overall, the effects of the 2 drugs on cell proliferation or autophagic death, either alone or in combination, were more pronounced in cells that harbored genetic alterations in the MAP kinase and PI3K/Akt pathways. Thus, these results demonstrated the important therapeutic potential of the novel MEK inhibitor RDEA119 and its synergism with temsirolimus in thyroid cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Diphenylamine; Drug Synergism; Flow Cytometry; Humans; MAP Kinase Kinase Kinases; Mice; Mice, Nude; Mutation; Proto-Oncogene Proteins B-raf; Sirolimus; Sulfonamides; Thyroid Neoplasms; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Mantle cell lymphoma is a highly malignant non-Hodgkin's lymphoma. There is no consensus on chemotherapy regimens for patients who do not qualify for haematopoietic stem cell transplantation. Temsirolimus, a metabolic precursor of sirolimus, already marketed in the European Union for metastatic kidney cancer, recently received an extension of indications to include relapsed or refractory mantle cell lymphoma. In this setting, one trial involving 162 patients in whom 2 or 3 chemotherapy regimens had failed compared two doses of temsirolimus (175 mg per week for 3 weeks, followed by 75 mg or 25 mg per week) versus a control group receiving various other treatments. The median overall survival time was about 11 months, regardless of the treatment.The median survival time before radiological or clinical progression was slightly longer with the higher dose of temsirolimus than in the control group (4.8 versus 1.9 months). Both of the temsirolimus dose regimens were highly toxic: 5 deaths, haematological disorders in more than 90% of patients, and haemorrhage or severe thrombocytopenia in about 50% of cases. Reactions during the infusion, infections, mucositis, fatigue and diarrhoea were also frequent.The cytochrome P450 isoenzyme CYP 3A4 is involved in temsirolimus metabolism, hence a high risk of pharmacokinetic interactions. The packaging is inappropriate and represents a potential source of dosing errors. In practice, temsirolimus shows only limited efficacy but is highly toxic in patients with relapsed or refractory mantle cell lymphoma after several prior chemotherapy regimens. It is better to avoid using this drug.

Topics: Antineoplastic Agents; Drug Packaging; Humans; Lymphoma, Mantle-Cell; Sirolimus

To detail tolerance of temsirolimus in a routine practice setting within a compassionate use program for patients with renal cell carcinoma.. We treated 32 patients with advanced renal cell carcinoma with temsirolimus within the German compassionate use program on an individual patient basis free of charge according to EU guidelines at our two institutions. Twenty-five milligrams of temsirolimus was applied weekly in an inpatient clinical setting. Adverse events were classified following National Cancer Institute Common Toxicity Criteria.. No dose modification or therapy interruptions were necessary due to adverse events. Adverse events like asthenia/fatigue were observed in 43.8%, increased creatinine in 40.6%, mucositis in 31.3%, secondary diabetes in 28.1%, hypothyreosis in 12.5% and rash in 12.5%, hypercholesterolemia and hypertriglyceridemia in 9.3% of the patients.. Therapy with temsirolimus in advanced renal cell carcinoma is well tolerated. In a routine practice setting it results in a predictable adverse event profile that can be managed medically.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Administration Schedule; Female; Germany; Government Programs; Health Services Accessibility; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Sirolimus

Since the late 1990s and the rapid expansion of monoclonal antibodies and synthetic protein kinase inhibitors in oncology, anticancer natural products fell out of fashion with the pharmaceutical industry. But in 2007 with the approval of three new drugs derived from natural products, the emergence of promising antitumor compounds from microorganisms (e.g. alvespimycin, salinosporamide) and the growing importance of new formulations of known natural product-derived drugs (nanoparticle formulations, oral forms), we are witnessing a new wave for natural products in oncology. The recent approval of the microtubule-targeted epothilone derivative ixabepilone (Ixempra), the DNA-alkylating marine alkaloid trabectedin (Yondelis) and the inhibitor of mTOR protein kinase temsirolimus (Torisel) is emblematic of the evolution of the field which combines the long established finding of conventional cytotoxic agents and the emergence of molecularly targeted therapeutics. These three examples also illustrate the increasing importance of microbial sources for the discovery of medically useful natural products. The contribution of innovative biological targets is also highlighted here, with references to proteasome inhibitors and novel approaches such as manipulation of mRNA splicing. Altogether, these observations plead for the return of natural products in oncology.

Topics: Antineoplastic Agents; Biological Products; Dioxoles; Epothilones; Humans; Neoplasms; Sirolimus; Tetrahydroisoquinolines; Trabectedin

With the introduction of targeted therapies, a paradigm shift for the treatment of metastatic renal cell cancer has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards. An interdisciplinary consensus conference was held to discuss treatment sequences and open questions. Results from the 2007 conference provided the basis for the 2008 meeting. The results of the 2008 conference are presented as short theses.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Indoles; Kidney; Kidney Neoplasms; Neoadjuvant Therapy; Neoplasm Metastasis; Nephrectomy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Risk Assessment; Risk Factors; Sirolimus; Sorafenib; Sunitinib; Time Factors

A 58-year-old man with advanced renal cell carcinoma developed grade 3 proteinuria (8.5 g/24 h) without microscopic hematuria or renal insufficiency five days after temsirolimus infusion. Kidney biopsy revealed ischemic glomeruli and focal segmental glomerulosclerosis lesion. Proteinuria level decreased to 2.80 g per day two weeks after temsirolimus withdrawal. Clinicians should be aware to this complication.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Glomerulosclerosis, Focal Segmental; Humans; Kidney Neoplasms; Male; Middle Aged; Proteinuria; Sirolimus

The Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers and plays an important role in small cell lung cancer (SCLC) biology. We investigated the potential of targeting mTOR signaling as a novel antitumor approach in SCLC.. The expression of mTOR in patient specimens and in a panel of SCLC cell lines was analyzed. The effects on SCLC cell survival and downstream signaling were determined following mTOR inhibition by the rapamycin derivative RAD001 (Everolimus) or down-regulation by small interfering RNA.. We found elevated expression of mTOR in patient specimens and SCLC cell lines, compared with normal lung tissue and normal lung epithelial cells. RAD001 treatment impaired basal and growth factor-stimulated cell growth in a panel of SCLC cell lines. Cells with increased Akt pathway activation were more sensitive to RAD001. Accordingly, a constitutive activation of the Akt/mTOR pathway was sufficient to sensitize resistant SCLC cells to the cytotoxic effect of RAD001. In the sensitive cells, RAD001 showed a strong additive effect to the proapoptotic action of the chemotherapeutic agent etoposide. Intriguingly, we observed low Bcl-2 family proteins levels in the SCLC cells with a constitutive Akt pathway activation, whereas an increased expression was detected in the RAD001-resistant SCLC cells. An antisense construct targeting Bcl-2 or a Bcl-2-specific inhibitor was able to sensitize resistant SCLC cells to RAD001. Moreover, SCLC tumor growth in vivo was significantly inhibited by RAD001.. Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells.

Topics: Animals; Antineoplastic Agents; Carcinoma, Small Cell; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Drug Resistance, Neoplasm; Etoposide; Everolimus; Humans; Lung Neoplasms; Mice; Protein Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sirolimus; Stem Cell Factor; TOR Serine-Threonine Kinases

For almost the last two decades, interleukin-2 and interferon-alpha have been the only systemic treatment options available for metastatic renal cell carcinoma. However, in recent years, five new targeted therapies namely sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab have demonstrated clinical activity in these patients. With the availability of new targeted agents that are active in this disease, there is a need to continuously update the treatment algorithm of the disease. Due to the important advances obtained, the Spanish Oncology Genitourinary Group (SOGUG) has considered it would be useful to review the current status of the disease, including the genetic and molecular biology factors involved, the current predicting models for development of metastases as well as the role of surgery, radiotherapy and systemic therapies in the early- or late management of the disease. Based on this previous work, a treatment algorithm was developed.

Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Humans; Indoles; Kidney Neoplasms; Linear Models; Neoplasm Metastasis; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Pyrroles; Receptor Protein-Tyrosine Kinases; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factors

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Drug Monitoring; Humans; Neuroendocrine Tumors; Octreotide; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

A flurry of reports indicates that we are entering a new phase in the development of mammalian target of rapamycin (mTOR)-based therapies for oncology. Here, we summarize exciting findings regarding mTOR signaling and the outlook for mTOR inhibitors as tools to study the mTOR pathway and as drugs in the clinic.

Topics: Everolimus; Humans; Immunosuppressive Agents; Mechanistic Target of Rapamycin Complex 1; Models, Biological; Multiprotein Complexes; Phosphatidylinositol 3-Kinases; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Proteins; Signal Transduction; Sirolimus; Tacrolimus Binding Protein 1A; TOR Serine-Threonine Kinases; Transcription Factors

To be a reliable predictor of response, tracer uptake should reflect changes in the amount of active tumor cells. However, uptake of (18)F-FDG, the most commonly used PET tracer, is disturbed by the inflammatory cells that appear early after cytotoxic therapy. The first aim of this study was to investigate whether 3'-(18)F-fluoro-3'-deoxy-l-thymidine ((18)F-FLT), a marker of cellular proliferation, is a better tracer for response assessment early after cytotoxic therapy. A second objective of this study was to investigate whether (18)F-FDG and (18)F-FLT responses were comparable early after mammalian target of rapamycin (mTOR) inhibition, as an example of proliferation-targeting therapies.. Severe combined immunodeficient mice were subcutaneously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. Half the mice were treated with cyclophosphamide and the other half with mTOR inhibition. (18)F-FDG and (18)F-FLT uptake was evaluated by small-animal PET on day 0 (D0; before treatment), D+1, D+2, D+4, D+7, D+9, D+11, and D+14. At each time point, 2 mice of each treatment condition were sacrificed, and tumors were excised for histopathology.. After cyclophosphamide, (18)F-FDG and (18)F-FLT uptake decreased, with a maximum reduction of -29% for (18)F-FDG and -25% for (18)F-FLT uptake at D+2, compared with baseline. Although (18)F-FDG uptake increased from D+4 on, with a maximum on D+7, (18)F-FLT uptake remained virtually stable. Histology showed an increase in apoptotic or necrotic tumor fraction, followed by an influx of inflammatory cells. In mTOR-inhibited mice, (18)F-FDG uptake dropped until D+2 after therapy (-43%) but increased at D+4 (-27%) to form a plateau on D+7 and D+9 (-14% and -16%, respectively). Concurrently, (18)F-FLT uptake decreased to -31% on D+2, followed by an increase with a peak value of +12% on D+7, after which (18)F-FLT uptake decreased again. Cyclin D1 expression dropped from D+1 until D+4 and returned to baseline at D+7.. Because (18)F-FLT uptake is not significantly influenced by the temporary rise in inflammatory cells early after cyclophosphamide, it more accurately reflects tumor response. However, a formerly unknown temporary rise in (18)F-FLT uptake a few days after the administration of mTOR inhibition was defined, which makes it clear that drug-specific responses have to be considered when using PET for early treatment monitoring.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cyclophosphamide; Dideoxynucleosides; Fluorodeoxyglucose F18; Humans; Lymphoma; Metabolic Clearance Rate; Mice; Mice, SCID; Protein Kinase Inhibitors; Protein Kinases; Radionuclide Imaging; Radiopharmaceuticals; Sirolimus; Tissue Distribution; TOR Serine-Threonine Kinases; Treatment Outcome

It has been previously shown that blockade of the type 1 insulin-like growth factor receptor (IGF1R) signaling combined with mTOR inhibition decreased neuroblastoma proliferation in vitro. MYC-N inactivation occurs through phosphorylation by downstream elements of the IGF1R signaling pathway. It was hypothesized that inhibition of IGF1R signaling would increase the inactivation of MYC-N.. BE-2(c) and IMR-32 neuroblastoma cell lines were treated with varying concentrations of alphaIR3, rapamycin and temsirolimus either alone or in combination and the expression of MYC-N and phosphorylated MYC-N proteins were evaluated by Western blotting. The number of apoptotic cells was evaluated through cleaved caspase-3 expression.. IGF1R signaling blockade in combination with mTOR inhibition decreased MYC-N protein expression, increased MYC-N phosphorylation and significantly increased cleaved caspase-3 expression in treated cells.. The combination of rapamycin or temsirolimus with alphaIR3 decreases MYC-N expression, increases MYC-N phosphorylation and induces apoptosis in vitro which may have clinical relevance to children with neuroblastoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Humans; N-Myc Proto-Oncogene Protein; Neuroblastoma; Nuclear Proteins; Oncogene Proteins; Phosphorylation; Receptor, IGF Type 1; Signal Transduction; Sirolimus; Tumor Cells, Cultured

To determine if the mammalian target of rapamycin (mTOR) inhibitor CCI-779 can sensitize head and neck squamous cell carcinoma (HNSCC) to radiotherapy (XRT) and compare the radiosensitizing effects to cisplatin with its known considerable toxicity. Radiosensitizing effects of CCI-779 were assayed on HNSCC cell lines in vitro. CCI-779 (5 mg/kg), cisplatin (1 mg/kg), and XRT (2 Gy) alone and in combination were evaluated for antitumor activity in mice bearing FaDu and SCC40 xenografts. Effects of CCI-779 on radiation-induced activation of the Akt/mTOR pathway were analyzed. Although CCI-779 did not sensitize HNSCC cells to ionizing radiation in vitro, combination of CCI-779 and XRT significantly augmented the in vivo tumor growth-inhibitory effects of XRT and CCI-779 (P < 0.05). In addition, CCI-779 + XRT suppressed tumor growth more effectively than cisplatin + XRT (P < 0.05). CCI-779 + XRT significantly improved survival compared with XRT alone in both cisplatin-sensitive FaDu (P < 0.01) and cisplatin-resistant SCC40 (P < 0.05) xenograft mice. There were no additional benefits of adding cisplatin to CCI-779 + XRT. CCI-779 significantly attenuated irradiation-induced up-regulation of the mTOR pathway, increased apoptosis and displayed potent antiangiogenic activity in FaDu xenografts that was further enhanced by its combination with XRT (P < 0.05), which may explain the mechanism of its selective radiosensitizing effects in vivo and not in vitro. Antitumor activity of XRT was enhanced when combined with CCI-779 in HNSCC xenograft model. CCI-779 + XRT showed antitumor activity superior to conventional chemoradiotherapy with cisplatin. These results pave the way for clinical trials using molecular targeted therapy with CCI-779 in combination with XRT for HNSCC treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cisplatin; Combined Modality Therapy; Head and Neck Neoplasms; Mice; Mice, Inbred Strains; Protein Kinases; Radiation-Sensitizing Agents; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Fatal Outcome; Humans; Kidney Neoplasms; Male; Sirolimus; Treatment Outcome

We present a case of a 73-year-old female with metastatic renal cell carcinoma, clear cell histologic subtype, who developed pruritic rash after 2 weeks of 25 mg weekly infusions of temsirolimus. Rash was located on bilateral antecubital areas and posterior knees. Skin biopsy showed spongiotic dermatitis with eosinophils. Based on history and clinical examination, a diagnosis of drug rash secondary to temsirolimus was made. Temsirolimus is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR). Inhibition of mTOR kinase results in cell cycle arrest, antiangiogenesis, and apoptosis. The mechanism of skin toxicity is unknown; however, it can be hypothesized that there is a direct inhibitory effect on signaling pathways that regulate cell growth and tissue repair. The mTOR kinase inhibitor temsirolimus has shown great promise in increasing overall survival in patients with metastatic renal cell carcinoma. Dermatologic toxicities are among the most prevalent and necessitate early recognition and management, in order to maintain quality of life and consistent therapy. The patient presented was initiated on topical clobetasol resulting in rash resolution at a 2-week follow-up visit.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Eosinophils; Exanthema; Female; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

To investigate the effect of the mammalian target of rapamycin (mTOR) inhibitor CCI-779 on the chemosensitivity of androgen-independent prostate cancer cell line PC-3.. Prostate cancer cells PC-3 were cultured and treated with CCI-779, Paclitaxel and combination of the two. Then the inhibitory effects of the three medications on the growth of the PC-3 cells were determined by MTT, and the their cell cycle and apoptosis were detected by flow cytometry.. Compared with the control group, the three medications all significantly inhibited the proliferation of the PC-3 cells, and the combined method even enhanced the effect. Flow cytometry showed that CCI-779 and Paclitaxel blocked the cell cycle mainly in the G1/G2 stage, while the combined medication mainly in the G0/G1 stage. Significantly increased apoptosis of the PC-3 cells was observed in the three medication groups as compared with the control group (P < 0.01).. CCI-779 can inhibit the proliferation of PC-3 cells and enhance the chemosensitivity of prostate cancer.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Drug Therapy, Combination; Humans; Male; Paclitaxel; Prostatic Neoplasms; Protein Kinase Inhibitors; Sirolimus

The macrolide sirolimus (rapamycin) selectively blocks translation of mRNAs containing a terminal 5' oligopyrimidine (TOP) tract by altering the activity of mammalian target of rapamycin (mTOR) and inhibiting downstream mTOR pathway components involved in TOP mRNA translation. The skin disorder pachyonychia congenita (PC) is caused by mutations in the inducible keratins (K) including K6a, K6b, K16 and K17. Published sequence data suggest the 5' untranslated regions of K6a and K6b mRNAs contain 5' TOP motifs and therefore may be sensitive to rapamycin treatment.. Determine if mTOR inhibitors (rapamycin, temsirolimus or everolimus) are viable drug candidates for treatment of PC and other disorders caused by inappropriate expression of K6a and K6b.. 5' RACE analysis was used to map the transcriptional start sites for K5, K6a, K6b, K14, K16 and K17. The sensitivity of these keratins to mTOR inhibitors was determined by Western and qPCR analysis following treatment of a human HaCaT keratinocyte cell line with rapamycin, temsirolimus or everolimus. A small off-label study was undertaken using orally administered rapamycin in three PC patients and the effects were monitored by clinical examination, photography, a validated Dermatology Life Quality Index (DLQI) and a pain and activity diary.. Sequence comparison and 5' RACE analysis of the 5' untranslated regions of K6a and K6b revealed putative TOP regulatory elements. Treatment of a human HaCaT keratinocyte cell line with mTOR inhibitors (rapamycin, temsirolimus or everolimus) resulted in selective K6a repression. Furthermore, treatment of this HaCaT cell line with siRNAs targeting components of the mTOR pathway altered the levels of K6a expression. To test the ability of rapamycin to ameliorate PC symptoms, an off-label study was conducted. PC patient clinical responses to oral rapamycin showed a therapeutic response in callus character as well as subjective improvement. Of particular note, rapamycin greatly reduced the presence of painful cutaneous thromboses after reaching therapeutic serum levels. The well-known rapamycin side effects led to the early withdrawal of all of the patients from the study.. Rapamycin selectively blocks K6a expression in human keratinocytes. The improvement of symptoms in PC patients following rapamycin treatment suggests rapamycin (or rapamycin analogs) may be a therapeutic option, particularly if topical formulations can be developed that avoid the side effects associated with systemic administration.

Topics: 5' Untranslated Regions; Administration, Oral; Base Sequence; Cell Line; Dose-Response Relationship, Drug; Everolimus; Female; Gene Expression Regulation; Humans; Keratin-6; Keratinocytes; Molecular Sequence Data; Pachyonychia Congenita; Pain; Pain Measurement; Protein Kinases; Quality of Life; RNA 5' Terminal Oligopyrimidine Sequence; RNA Interference; RNA, Messenger; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Transcription Initiation Site; Transcription, Genetic; Treatment Outcome

We investigated the genotype-dependent therapeutic potential of targeting the phosphoinositide 3-kinase (PI3K)/Akt pathway for thyroid cancer. Proliferation of TPC1, Hth7, FTC133, OCUT1, K1, and BCPAP cells that harbored PI3K/Akt-activating genetic alterations was potently inhibited by the Akt inhibitor perifosine, whereas SW1736, Hth74, WRO, KAT18, and TAD2 cells that harbored no genetic alterations had no or only modest responses. Inhibition of Akt phosphorylation by perifosine was seen in these cells. Genetic-dependent apoptosis was induced by perifosine in cells selectively tested. Similarly, potent inhibition of cell proliferation by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus occurred in virtually all the cells harboring genetic alterations, whereas modest inhibition was seen in some of the cells not harboring genetic alterations. Temsirolimus inhibited the phosphorylation of p70S6K, a substrate of mTOR. Knockdown of Akt1/2 or mTOR by shRNA approach inhibited the proliferation and colony formation of FTC133 and OCUT1 cells that harbored genetic alterations in the PI3K/Akt pathway but had no effect on SW1736 and KAT18 cells that did not. Transfection with PIK3CA mutants greatly sensitized SW1736 cells to perifosine and temsirolimus. Growth of xenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine. Thus, this work for the first time shows that genetic alterations in the PI3K/Akt pathway confer thyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR. This genotype-based targeting of the PI3K/Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for thyroid cancer and warrants further studies.

Topics: Animals; Cell Growth Processes; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Humans; Mice; Mice, Nude; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylcholine; Protein Kinases; RNA, Small Interfering; Signal Transduction; Sirolimus; Thyroid Neoplasms; TOR Serine-Threonine Kinases; Transfection; Xenograft Model Antitumor Assays

Optimal scheduling of cycle-active chemotherapy with (initially cytostatic) molecular-targeted agents is important to maximize clinical benefit. Concurrent scheduling might allow up-regulation of cell death pathways at the time of chemotherapy, whereas sequential treatments might maximize inhibition of repopulation and avoid putting tumor cells out of cycle when administering cycle-active chemotherapy. We compared the effects of concurrent and sequential administration of chemotherapy and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus (CCI-779) on tumor cells and xenografts.. Human prostate cancer PC-3 and LnCaP, and human breast cancer MDA-468 cells and xenografts were treated with chemotherapy (docetaxel and 5-fluorouracil, respectively) and temsirolimus, using concurrent and sequential treatment schedules. Cell killing and repopulation were evaluated by clonogenic assays. Cell cycle analysis was done using flow cytometry. Effects on xenografts were assessed by tumor growth delay.. The proliferation of all cell lines was inhibited by temsirolimus in a dose-dependent manner; PTEN negative PC-3 and mutant LnCaP cells were more sensitive than PTEN-negative MDA-468 cells. Temsirolimus inhibited cell cycle progression from G(1) to S phase in all cell lines. Combined treatment had greater effects than temsirolimus or chemotherapy alone: for PC-3 and LnCaP xenografts, concurrent treatment seemed superior to sequential scheduling, whereas MDA-468 cells and xenograft tumors did not show schedule dependence.. Combined treatment with temsirolimus and chemotherapy had a greater therapeutic effect than monotherapy; concurrent scheduling was more effective for PC-3 and LnCaP cells and xenografts that were sensitive to temsirolimus.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Docetaxel; Drug Synergism; Female; Fluorouracil; Humans; Male; Mice; Mice, Nude; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; Taxoids; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Topics: Acute Kidney Injury; Antineoplastic Agents; Carcinoma; Humans; Kidney Neoplasms; Male; Middle Aged; Sirolimus

Topics: Antineoplastic Agents; Clinical Trials as Topic; Disease Progression; Humans; Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) is implicated in cell growth especially during cancer development and progression. Its action is dependent on well known oncogenic pathways that regulate tumor cell growth and cell cycle progression, in response to different stimuli. Sirolimus, temsirolimus and everolimus are specific inhibitors of mTOR that have originally been characterized by their antifungal and immunosuppressive properties, but also significantly inhibit cancer cells'proliferation, invasion, and metastasis, and promote apoptosis. In addition, mTOR inhibitors display potent antiangiogenic properties by the suppression of vascular endothelial growth factor signal transduction. The antitumoral effects of mTOR inhibitors, as a monotherapy or in combination with tyrosine kinase inhibitors or usual cytotoxic agents, have been extensively suggested in preclinical studies, including animal models. In a clinical setting, preliminary reports have demonstrated that mTOR inhibitors use is associated with an acceptable safety profile. Currently, mTOR inhibitors are tested in multiple trials and various cancer types, usually in intermittent schedules to avoid significant immunosuppression. Of particular interest is the use of mTOR inhibitors in the field of organ transplantation, including liver transplantation, in preventive or curative strategies, for the treatment of recurrent hepatocellular carcinoma and de novo post-transplantation malignancies.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Everolimus; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Liver Transplantation; Neoplasm Invasiveness; Neoplasm Metastasis; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Quinolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Down-regulation by small interfering RNA or absence of hypoxia-inducible factor (HIF-1alpha) has been shown to lead to increased sensitivity to glycolytic inhibitors in hypoxic tumor cells. In surveying a number of tumor types for differences in intrinsic levels of HIF under hypoxia, we find that the reduction of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung cancer cell lines when treated under hypoxia. Because HIF-1alpha translation is regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR and AKT activity and found that HIF-1alpha down-regulation coincided with increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG toxicity in cell lines that did not express HIF. These results support the hypothesis that although mTOR inhibition leads to the blockage of numerous downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1alpha. Overall, our findings show that CCI-779 hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, may be important in dictating the decision on how best to use 2-DG alone or in combination with CCI-799 to kill hypoxic tumor cells clinically.

Topics: Cell Hypoxia; Cell Line, Tumor; Deoxyglucose; Down-Regulation; Drug Screening Assays, Antitumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Mutation; Protein Kinases; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases

In this article, you'll learn about eight new drugs, including: doripenem, an antibiotic for complicated intra-abdominal and urinary tract infections. Maraviroc, a new antiretroviral agent to treat HIV infection. Ixabepilone, a new drug for refractory metastatic breast cancer. Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug's safety during pregnancy and breast-feeding. Also consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for all these drugs.

Topics: Acromegaly; Adult; Anti-Bacterial Agents; Anti-HIV Agents; Antineoplastic Agents; Biopterins; Carbapenems; Child; Child, Preschool; Cyclohexanes; Doripenem; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Epothilones; Humans; Infant; Maraviroc; Peptides, Cyclic; Pharmaceutical Preparations; Phenylketonurias; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Sirolimus; Somatostatin; Triazoles

We show that cisplatin resistance in certain lung cancer cell lines can be reversed through inhibition of mTOR (mammalian Target of Rapamycin). These cell lines appear to possess high levels of phospho-mTOR, phospho-AKT and other growth-related proteins, such as hTERT (human telomerase reverse transcriptase), and Cyclin D3 which decrease upon inhibition of mTOR. Interestingly in one cisplatin resistant cell line which expresses BCL2/BCLxL, treatment with mTOR inhibitor (CCI-779) results in decreased levels of these anti-apoptotic proteins and may contribute to increasing apoptosis. Moreover, continuous exposure to CCI-779 was found to increase the expression of the multi-drug resistant P-gp1(P-gycoprotein1) efflux pump and therefore should be taken into consideration when designing clinical trials with this compound.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; bcl-X Protein; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Line, Tumor; Cisplatin; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-bcl-2; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Sirolimus

Topics: Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Drug Delivery Systems; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Drug Approval; Drug Costs; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; State Medicine; Sunitinib; United Kingdom

Although medical treatment for advanced renal cell carcinoma has included cytokine therapies such as interferon and interleukin-2, the treatment system has been revolutionized with the emergence of molecular target medicine. A vascular endothelial growth factor and its receptor for the target molecule are the mainstream, but the efficacy of inhibitors of an alternate pathway has been established. It seems that even newer molecular target medicine will be introduced in the future, but the optimal medicine based on the individual condition must be provided in renal cell carcinoma cases.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Immunotherapy; Indoles; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Once surgical options have been exhausted, systemic therapy is indicated for metastasizing renal cell carcinoma. Until recently this was carried out using mainly immunotherapeutic concepts with unsatisfactory results. Since the majority of clear cell renal cell carcinomas are well vascularised, angiogenetic inhibition offered an alternative therapy goal. To date, four substances have been approved to control angiogenesis in the therapy of renal cell carcinoma: sunitinib, sorafenib, temsirolimus, as well as a combination of bevacizumab and interferon alpha. Other substances, such as everolimus, pazopanib and axitinib, are currently the subject of clinical trials. Initial data on tolerance and efficacy was presented at this years annual conference of the American Society of Clinical Oncology (ASCO). This article examines current therapy options and ASCO data and discusses future trends.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Humans; Indoles; Interferon-alpha; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Tomography, X-Ray Computed

mTOR interacts with multiple proteins involved in major signal transduction pathways controlling cell growth, proliferation, and apoptosis. mTOR is acknowledged to play major roles in cellular interplays between cancer and stroma cells, including endothelial cells. Rapalogues demonstrated antitumour activity in several hypervascularized tumours in clinical trials. Whether rapalogues directly affect cancer cells or other stroma cells in tumours remains poorly understood. Knowing whether rapalogues act directly against cancer cells and/or could be considered as antiangiogenic agents has major implications in terms of medical indications and may help to further improve their drug development. Herein, we hypothesize that current rapalogues demonstrating activity in hypervascularized tumours may primarily act through antiangiogenic effects in patients, a hypothesis that certainly requires further translational investigations.

Topics: Angiogenesis Inhibitors; Animals; Humans; Kidney Neoplasms; Sirolimus

Topics: Administration, Oral; Antibiotics, Antineoplastic; Area Under Curve; Carcinoma, Renal Cell; Disease Progression; Drug Administration Schedule; Humans; Kidney Neoplasms; Neoplasm Metastasis; Renal Dialysis; Sirolimus; Time Factors; Treatment Outcome

The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Several mTOR inhibitors are currently being tested in cancer clinical trials. Both PI3K/Akt and MEK/ERK signaling regulate mTOR axis. However, inhibition of mTOR activates Akt survival signaling, which in turn attenuates mTOR inhibitors' anticancer efficacy. We are interested in developing strategies for enhancing mTOR-targeted cancer therapy. In this study, we report that mTOR inhibition also induced activations of the MEK/ERK signaling pathway in some cancer cell lines after a prolonged treatment. The combination of rapamycin with the MEK inhibitor U0126 significantly enhanced growth inhibitory effects of cancer cells, suggesting that MEK/ERK activation may counteract mTOR inhibitors' anticancer efficacy. Similarly, the combination of an mTOR inhibitor with the EGF receptor inhibitor erlotinib synergistically inhibited the growth of both human cancer cells in cell cultures and xenografts in nude mice. Moreover, the presence of erlotinib suppressed rapamycin-induced phosphorylation of Akt, ERK and eIF4E as well, implying that erlotinib can suppress mTOR inhibition-induced feedback activation of several survival signaling pathways including Akt, ERK and eIF4E. Thus, we suggest a therapeutic strategy for enhancing mTOR-targeted cancer therapy by preventing mTOR inhibition-induced feedback activation of several survival mechanisms.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Enzyme Inhibitors; Erlotinib Hydrochloride; Extracellular Signal-Regulated MAP Kinases; Humans; Kidney Neoplasms; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Quinazolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Patients with metastatic renal cell carcinoma (RCC) generally show a poor prognosis; treatment approaches have not significantly improved patient survival. Temsirolimus inhibits the mammalian target of rapamycin kinase. Clinical studies have shown positive results when the drug is administered to patients with this disease. The clinical benefit of temsirolimus for poor-risk, advanced RCC patients was demonstrated in a Phase III study comparing temsirolimus with interferon alpha (IFN-alpha) or combined temsirolimus plus IFN-alpha as first-line treatment of advanced RCC, showed that treatment with temsirolimus alone significantly increased median overall survival in poor-risk, advanced RCC patients (10.9 vs 7.3 vs 8.4 months). This was the first Phase III trial to demonstrate an overall improvement in survival using an agent as "targeted therapy" for patients with advanced RCC. By November 2007, 200 patients with advanced RCC had been treated with temsirolimus before its approval by the European Medicines Agency (EMEA) within a compassionate use program. The single-center treatment experiences using temsirolimus in patients for compassionate use are described herein. The treatment was generally well tolerated; side effects (mucositis, diabetes, and peripheral edema) were within the range expected from the pivotal trials and manageable with supportive care. Further development strategies for temsirolimus in patients with RCC include its evaluation with bevacizumab and also as second-line therapy in patients who have failed first-line therapy with sunitinib.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Kidney Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Survival Analysis; Survivors

(1) Most kidney tumours are discovered at an advanced stage or after they have already metastasised. Even in these cases, surgical excision, when feasible, remains the first-line treatment. Chemotherapy only increases survival time by a few months, at a cost of frequent adverse effects. The best-assessed drug in this setting is interferon alfa; (2) Temsirolimus is marketed for first-line treatment of advanced-stage kidney cancer in patients who have risk factors associated with a poor prognosis. Temsirolimus is a water-soluble derivative of sirolimus. After intravenous administration it is rapidly metabolised into sirolimus; (3) Clinical evaluation is based on a randomised unblinded trial in 626 patients with kidney cancer. Nearly all of the patients had metastases, and all had at least 3 of the 6 risk factors associated with poor outcome. The median survival time was significantly longer with temsirolimus monotherapy than with interferon alfa-2a monotherapy (10.9 versus 7.3 months), but it was not longer with interferon alfa-2a + temsirolimus than with interferon alfa-2a alone; (4) There were fewer severe adverse events with temsirolimus than with interferon alfa-2a (66.8% versus 77.5% of patients, respectively). Yet temsirolimus provokes several serious adverse effects, such as hyperglycaemia, hypophosphataemia, and hypokalaemia. Other adverse effects include hypersensitivity reactions, bleeding and infections; (5) Temsirolimus is metabolised by cytochrome P450 isoenzyme CYP 3A4, creating a risk of pharmacokinetic interactions; (6) In practice, the only evidence supporting the efficacy of temsirolimus is based on a single unblinded trial. Adverse effects are frequent and sometimes serious. Additional comparative trials are needed.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Therapy, Combination; Europe; Humans; Interferon alpha-2; Interferon-alpha; Kidney Neoplasms; Neoplasm Metastasis; Recombinant Proteins; Sirolimus; Treatment Outcome

Topics: Antineoplastic Agents; Drug Interactions; Everolimus; Humans; Kidney Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

To investigate the mechanisms of antiproliferative effect induced by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus in mantle cell lymphoma (MCL).. The antiproliferative effect of temsirolimus on three well-defined MCL cell lines was examined by the MTS assay. Induction of cell-cycle arrest, autophagy, and apoptosis were determined by fluorescence-activated cell sorting analysis. The molecular mechanisms underlining these effects were determined by Western blot. Synergy between temsirolimus and vorinostat were examined by MTS assay and the combination index was calculated.. Temsirolimus has antiproliferative activity in three MCL cell lines in a dose- and time-dependent manner. Mechanistically, temsirolimus inhibited mTOR, as evidenced by inhibition of ribosomal S6 phosphorylation, and induced cell-cycle arrest in the G(0)/G(1) phase and a decrease in p21 expression without altering p27 or cyclin D1 levels. Furthermore, temsirolimus increased the number of acidic vesicular organelles and the amount of microtubule-associated protein 1 light-chain 3 processing, which are characteristic of autophagy, without induction of apoptosis. These changes were not associated with alteration in phosphorylated extracellular signal-regulated kinase (ERK), beclin-1, Bax, or Bak levels. In contrast, treatment of these cell lines with the histone deacetylase inhibitor vorinostat decreased ERK phosphorylation, activated caspase 3, and induced apoptosis. Moreover, temsirolimus synergized with submaximal concentrations of vorinostat in all MCL cell lines.. This is the first report of temsirolimus-induced autophagy in MCL, and of vorinostat inhibition of ERK phosphorylation in MCL. Collectively, these data suggest that the combination of temsirolimus and vorinostat have synergistic antiproliferative activity in MCL cells by distinctively targeting apoptosis and autophagy.

Topics: Antineoplastic Agents; Autophagy; Cell Line; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; G1 Phase; Humans; Hydroxamic Acids; Lymphoma, Mantle-Cell; Sirolimus; Vorinostat

The mammalian target of rapamycin (mTOR) inhibitor CCI-779 (temsirolimus) is a recently Food and Drug Administration-approved anticancer drug with efficacy in certain solid tumors and hematologic malignancies. In cell culture studies, CCI-779 at the commonly used nanomolar concentrations generally confers a modest and selective antiproliferative activity. Here, we report that, at clinically relevant low micromolar concentrations, CCI-779 completely suppressed proliferation of a broad panel of tumor cells. This "high-dose" drug effect did not require FKBP12 and correlated with an FKBP12-independent suppression of mTOR signaling. An FKBP12-rapamycin binding domain (FRB) binding-deficient rapamycin analogue failed to elicit both the nanomolar and micromolar inhibitions of growth and mTOR signaling, implicating FRB binding in both actions. Biochemical assays indicated that CCI-779 and rapamycin directly inhibited mTOR kinase activity with IC(50) values of 1.76 +/- 0.15 and 1.74 +/- 0.34 micromol/L, respectively. Interestingly, a CCI-779-resistant mTOR mutant (mTOR-SI) displayed an 11-fold resistance to the micromolar CCI-779 in vitro (IC(50), 20 +/- 3.4 micromol/L) and conferred a partial protection in cells exposed to micromolar CCI-779. Treatment of cancer cells with micromolar but not nanomolar concentrations of CCI-779 caused a marked decline in global protein synthesis and disassembly of polyribosomes. The profound inhibition of protein synthesis was accompanied by rapid increase in the phosphorylation of translation elongation factor eEF2 and the translation initiation factor eIF2 alpha. These findings suggest that high-dose CCI-779 inhibits mTOR signaling through an FKBP12-independent mechanism that leads to profound translational repression. This distinctive high-dose drug effect could be directly related to the antitumor activities of CCI-779 and other rapalogues in human cancer patients.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Line; Cell Line, Tumor; Colonic Neoplasms; Female; Humans; Kidney; Lung Neoplasms; Male; Prostatic Neoplasms; Protein Biosynthesis; Protein Kinases; Sirolimus; Tacrolimus Binding Protein 1A; TOR Serine-Threonine Kinases

Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (C(max)) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUC(sum) (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.

Topics: Adolescent; Adult; Antineoplastic Agents; Area Under Curve; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Enzyme Inhibitors; Female; Humans; Infusions, Intravenous; Ketoconazole; Male; Middle Aged; Sirolimus

Hepatocellular carcinoma (HCC) is resistant to chemotherapy. We reported that sirolimus, an mTOR inhibitor, has antiangiogenic properties in HCC. Since antiangiogenic therapy may enhance chemotherapy effects, we tested the antitumorigenic properties of sirolimus combined with doxorubicin in experimental HCC.. Morris Hepatoma (MH) cells were implanted into livers of syngeneic rats. Animals were assigned to sirolimus, pegylated liposomal doxorubicin, both combined or control groups. Tumoral growth was followed by MRI. Antiangiogenic effects were assessed by CD31 immunostaining and capillary tube formation assays. Cell proliferation was monitored in vitro by thymidine incorporation. Expression of p21 and phosphorylated MAPKAP kinase-2 was quantified by immunoblotting.. Animals treated with the combination developed smaller tumors with decreased tumor microvessel density compared to animals that received monotherapies. In vitro, inhibition of mTOR further impaired capillary formation in the presence of doxorubicin. Doxorubicin reduced endothelial cell proliferation; inhibition of mTOR accentuated this effect. Doxorubicin stimulated p21 expression and the phosphorylation of MAPKAP kinase-2 in endothelial cells. Addition of mTOR inhibitor down-regulated p21, but did not decrease MAPKAP kinase-2 phosphorylation.. Sirolimus has additive antitumoral and antiangiogenic effects when administered with doxorubicin. These findings offer a rationale for combining mTOR inhibitors with chemotherapy in HCC treatment.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aorta; Apoptosis; Carcinoma, Hepatocellular; Cells, Cultured; Disease Models, Animal; Doxorubicin; Endothelial Cells; Intracellular Signaling Peptides and Proteins; Liver Neoplasms, Experimental; Male; Neoplasm Transplantation; Oncogene Protein p21(ras); Phosphorylation; Polyethylene Glycols; Protein Serine-Threonine Kinases; Rats; Rats, Inbred ACI; Sirolimus; Transcription Factors

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Sirolimus

We recently demonstrated that the mammalian target of rapamycin (mTOR) inhibitor, CCI-779, curtailed the growth of a subcutaneous challenge of multiple myeloma (MM) cells in immunodeficient mice. This antitumor effect was associated with prevention of cell proliferation, induction of apoptosis and inhibition of angiogenesis. Interestingly, myeloma tumors with heightened AKT activation were particularly sensitive to a CCI-779-induced antitumor response. To investigate whether part of the differential sensitivity was due to an AKT-regulated effect on angiogenesis, we compared the effects of mTOR inhibitors against isogenic MM cell lines that only differ by their degree of AKT activity. In this model, heightened AKT activity significantly sensitized MM cells to the following inhibitory effects of mTOR inhibition: angiogenesis in vivo, vascular endothelial growth factor (VEGF) expression in vitro and in vivo and VEGF translation (but not transcription). Assessment of p70S6 kinase activity indicated that rapamycin induced comparable mTOR inhibition in both cell lines suggesting that an adverse effect on VEGF cap-dependent translation would be comparable. Internal ribosome entry site (IRES)-mediated cap-independent translation is a salvage pathway for protein expression when mTOR is inhibited, so we analyzed a possible regulatory role of AKT on VEGF IRES activity. We found that elevated AKT activity inhibited VEGF IRES function. These results support a mechanism whereby AKT prevents VEGF IRES activity in myeloma cells during mTOR inhibition resulting in a more complete abrogation of VEGF translation, and ultimately, angiogenesis.

Topics: Actins; Animals; Antineoplastic Agents; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, SCID; Multiple Myeloma; Neovascularization, Pathologic; Oncogene Protein v-akt; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Disease Progression; Humans; Neuroendocrine Tumors; Sirolimus; Treatment Outcome

The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin insensitive and was recently shown to regulate the prosurvival kinase AKT by phosphorylation on Ser473. We investigated the molecular effects of mTOR inhibition by the rapamycin derivatives (RDs) temsirolimus (CCI-779) and everolimus (RAD001) in acute myeloid leukemia (AML) cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation. This resulted in suppression of phosphorylation of the direct AKT substrate FKHR and decreased transcription of D-cyclins in AML cells. Similar observations were made in samples from patients with hematologic malignancies who received RDs in clinical studies. Our study provides the first evidence that rapamycin derivatives inhibit AKT signaling in primary AML cells both in vitro and in vivo, and supports the therapeutic potential of mTOR inhibition strategies in leukemias.

Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Cyclin D; Cyclins; Drug Screening Assays, Antitumor; Enzyme Activation; Everolimus; Gene Expression Regulation, Leukemic; Glucose Transporter Type 1; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Proteins; Proto-Oncogene Proteins c-akt; Rapamycin-Insensitive Companion of mTOR Protein; Regulatory-Associated Protein of mTOR; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription, Genetic; U937 Cells

At the present time, the optimal development of molecularly targeted anticancer agents is limited by the lack of clinically applicable tools to predict drug effects. This study aimed to develop methods that might be useful in predicting the efficacy of targeted agents in a novel model system of human pancreatic cancer. A series of xenografts were established in nude mice by implanting human pancreatic cancer tissue surgically resected from cancer patients. Animals were treated with the epidermal growth factor receptor inhibitor erlotinib, the mammalian target of rapamycin inhibitor temsirolimus, or vehicle. Tumor cells were sampled by fine-needle aspiration biopsy (FNAB) before (baseline, day 0) and at the completion of 28 days of treatment. Cells obtained at baseline were exposed to erlotinib or temsirolimus in short-term cell culture conditions (ex vivo). Western blot analysis was done to determine the degree of inhibition in the phosphorylation of extracellular signal-regulated kinase 1/2 and S6-ribosomal protein (downstream effectors of epidermal growth factor receptor and mammalian target of rapamycin, respectively) ex vivo and in vivo. Five of six xenografted tumors responded to temsirolimus, whereas only one tumor responded to erlotinib. The results of the ex vivo studies correctly predicted the pharmacodynamic effect of the agents in vivo as well as their gross antitumor effects. Finally, we showed the clinical feasibility of this approach, performing ex vivo assessment of drug-target response in FNAB samples from three patients with pancreatic cancer. Cancer cells obtained by FNAB, an established minimally invasive diagnostic procedure, can be used to test ex vivo the effects of targeted anticancer agents. These effects correlate with antitumor activity in vivo and may therefore provide an important tool applicable to clinical trials. Ultimately, an approach of this nature may facilitate the further refinement of patient selection in favor of individuals with molecular profiles, predicting a greater likelihood of therapeutic benefit.

Topics: Adenocarcinoma; Animals; Biopsy, Fine-Needle; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Humans; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Pancreatic Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Quinazolines; Sirolimus; Xenograft Model Antitumor Assays

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Dioxoles; Enzyme Inhibitors; Humans; Protein Kinases; Protein-Tyrosine Kinases; Sarcoma; Sirolimus; Tetrahydroisoquinolines; Thalidomide; TOR Serine-Threonine Kinases; Trabectedin; Vascular Endothelial Growth Factor A

Molecular therapeutics identifies an aberration in tumors to select patients that benefit from molecular targeted therapy. Overexpression of eIF4E in histologically "tumor-free" surgical margins of head and neck squamous cell cancer (HNSCC) patients is an independent predictor of recurrence and is functionally activated through the Akt/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibitors are cytostatic agents, best used in combination therapy, we hypothesize that they can be used as long-term single agents in an HNSCC model of minimal residual disease (MRD). CCI-779, an mTOR inhibitor, arrested growth of a phosphatase and tensin homologue deleted on chromosome 10 (PTEN) abnormal HNSCC cell line FaDu, inhibiting phosphorylation of 4E-binding protein 1, resulting in increased association with eIF4E and inhibition of basic fibroblast growth factor and vascular endothelial growth factor. Fluorescence in situ hybridization detected PTEN abnormalities in 68% of patient tumors and 35% of tumor-free margins. CCI-779 inhibited growth of established tumors in nude mice. However, in the MRD model, there were significant differences in the tumor-free rate between the control (4%) and the treatment group (50%), and the median tumor-free time was 7 versus 18 days, respectively (P < 0.0001). In those animals that formed tumors, CCI-779 caused a significant decrease in the tumor volume. The Kaplan-Meier curve showed that CCI-779 significantly increased survival (P < 0.0001). The mTOR pathway was inhibited in peripheral blood mononuclear cells potential surrogate markers of response to therapy. Stable transfection of FaDu with luciferase allowed us to monitor the effects of CCI-779 with bioluminescence imaging in the MRD model. These results pave the way for a clinical trial using targeted molecular therapy with CCI-779 as a single agent for mTOR-activated residual cells.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Drug Evaluation, Preclinical; Gene Dosage; Head and Neck Neoplasms; Humans; Mice; Neoplasm, Residual; Protein Kinase Inhibitors; Protein Kinases; PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indoles; Interferons; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Von Hippel-Lindau Tumor Suppressor Protein

The epidermal growth factor receptor (EGFR) is a validated target in squamous cell carcinoma (SCC) of the head and neck. Most patients, however, do not respond or develop resistance to this agent. Mammalian target of rapamycin (mTOR) is involved in the pathogenesis of SCC of the head and neck (SCCHN). This study aimed to determine if targeting mTOR in combination with EGFR is effective in SCC, and to develop early pharmacodynamic markers of efficacy. Two SCC cell lines, one resistant (HEP2) and one of intermediate susceptibility (Detroit 562) to EGFR inhibitors, were xenografted in vivo and treated with an mTOR inhibitor (temsirolimus), an EGFR inhibitor (erlotinib) or a combination of both. Temsirolimus exerted superior growth arrest in both cell lines than erlotinib. The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line. Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration (FNA) biopsies early after treatment using phospho MAPK, Phospho-P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination, the only group where regressions were seen. In conclusion, an mTOR inhibitor showed antitumor activity in EGFR-resistant SCC cell lines. Marked antitumor effects were associated with dual pathway inhibition, which were detected by early FNA biopsies.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Synergism; ErbB Receptors; Erlotinib Hydrochloride; Female; Gene Expression; Gene Expression Profiling; Growth Inhibitors; Head and Neck Neoplasms; Humans; Immunohistochemistry; Mice; Mice, Nude; Neovascularization, Pathologic; Protein Kinase Inhibitors; Protein Kinases; Quinazolines; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

This study set out to investigate the antitumor effects of a treatment strategy combining the mTOR inhibitor CCI-779 with cisplatin in vitro and in a human melanoma SCID mouse model.. In vitro 518A2, Mel-JUSO or 607B cell lines were incubated with CCI-779, cisplatin and CCI-779 plus cisplatin. Based on these results, a 4-group, parallel, controlled experimental study design was initiated in vivo. SCID mice were injected with melanoma cells, and after the development of tumors the mice received daily injections of CCI-779 or solvent. On treatment days 2 and 6 cisplatin or mock solution were administered.. In vitro a synergistic antitumor effect was observed for the treatment regimen of CCI-779 plus cisplatin. In SCID mice after 2 weeks of therapy with CCI-779 plus cisplatin 4 of 6 tumors of the 518A2 cell line were completely eradicated. In the two remaining 518A2 xenografts this treatment strategy reduced the tumor weight by 94 +/- 9% compared to solvent. CCI-779 plus cisplatin also exerted a significant antitumor effect in Mel-JUSO and 607B xenografts compared to mock-treated animals.. We provide circumstantial evidence that the use of CCI-779 plus cisplatin might qualify as a promising strategy in the treatment of human melanoma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Humans; Melanoma, Experimental; Mice; Mice, SCID; Neoplasm Transplantation; Sirolimus; Transplantation, Heterologous

With the emergence of novel angiogenesis inhibitors, we are moving to a new era for patients with metastasized renal cell carcinoma. Since the results achieved reflect more a modification of the natural course of the disease than a cure, past achievements should not be neglected. Low-risk patients with clear cell histology, especially those with pulmonary metastasis only, should still be offered cytokine therapy. For intermediate-risk patients sunitinib is the treatment of choice. For high-risk patients, temsirolimus has to date provided the most convincing data, its availability is however limited. Data with sorafenib and sunitinib in the high-risk group are still anecdotal. The toxicity profiles of these 2 drugs are different and might particularly relate to patients with known cardiovascular co-morbidity. No sufficient data are available regarding sequential use. After cytokine failure, sorafinib is the treatment of choice. Patients should preferably be treated within clinical trials to answer unaddressed questions. It is well known that the strict entry criteria used within the clinical studies were applied very flexibly when drugs have been approved. These aspects require a careful follow-up to ascertain optimal use and to prevent misuse. Finally, the costs of prolonged treatment will be enormous, and only meaningful survival advantages will convince the health authorities to make these new treatments available for all patients.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials as Topic; Cytokines; Drug Costs; Humans; Indoles; Kidney Neoplasms; Long-Term Care; Lung Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Survival Rate

This study compares the antineoplastic potential of a novel treatment strategy combining cell cycle inhibitor-779 (CCI-779) plus dacarbazine (DTIC) versus DTIC monotreatment, the current chemotherapeutic mainstay in combating metastatic melanoma. A controlled four-group parallel study design comprising 24-40 mice per tumor cell line was used in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. SCID mice were injected with 518A2, Mel-JUSO, or 607B human melanoma cells. After they developed tumors, mice received daily CCI-779 or solvent over 14 days. From treatment day 4-8 mice were additionally injected with DTIC or saline. Treatment with CCI-779 plus DTIC was superior to single agent DTIC in two out of three cell lines (P<0.05). The tumor weight reduction was 44+/-17 and 61+/-6% compared with DTIC monotreatment in Mel-JUSO and 607B melanomas, respectively (P<0.05). In contrast, in 518A2 xenotransplants, CCI-779 plus DTIC treatment was as effective as DTIC monotreatment. CCI-779 monotherapy exerted no statistically significant antitumor effect. Collectively, these data indicate that CCI-779 has the potential to increase the chemotherapeutic efficacy, as the combination of CCI-779 plus DTIC proved to be more efficacious compared to DTIC monotherapy in two out of three melanoma cell lines in vivo.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Apoptosis; Dacarbazine; Drug Therapy, Combination; Humans; Melanoma; Mice; Mice, SCID; Oncogene Protein v-akt; Protein Kinases; PTEN Phosphohydrolase; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The in vitro metabolism of temsirolimus, (rapamycin-42-[2,2-bis-(hydroxymethyl)]-propionate), an antineoplastic agent, was studied using human liver microsomes as well as recombinant human cytochrome P450s, namely CYP3A4, 1A2, 2A6, 2C8, 2C9, 2C19, and 2E1. Fifteen metabolites were detected by liquid chromatography (LC)-tandem mass spectrometry (MS/MS or MS/MS/MS). CYP3A4 was identified as the main enzyme responsible for the metabolism of the compound. Incubation of temsirolimus with recombinant CYP3A4 produced most of the metabolites detected from incubation with human liver microsomes, which was used for large-scale preparation of the metabolites. By silica gel chromatography followed by semipreparative reverse-phase high-performance liquid chromatography, individual metabolites were separated and purified for structural elucidation and bioactivity studies. The minor metabolites (peaks 1-7) were identified as hydroxylated or desmethylated macrolide ring-opened temsirolimus derivatives by both positive and negative mass spectrometry (MS) and MS/MS spectroscopic methods. Because these compounds were unstable and only present in trace amounts, no further investigations were conducted. Six major metabolites were identified as 36-hydroxyl temsirolimus (M8), 35-hydroxyl temsirolimus (M9), 11-hydroxyl temsirolimus with an opened hemiketal ring (M10 and M11), N- oxide temsirolimus (M12), and 32-O-desmethyl temsirolimus (M13) using combined LC-MS, MS/MS, MS/MS/MS, and NMR techniques. Compared with the parent compound, these metabolites showed dramatically decreased activity against LNCaP cellular proliferation.

Topics: Antibiotics, Antineoplastic; Biotransformation; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Humans; In Vitro Techniques; Indicators and Reagents; Magnetic Resonance Spectroscopy; Mass Spectrometry; Microsomes, Liver; Recombinant Proteins; Sirolimus; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Indoles; Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Technology Transfer; Treatment Outcome

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Pyrroles; Sirolimus; Sunitinib

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Humans; Interferon-alpha; Kidney Neoplasms; Research Design; Sirolimus; Survival Analysis

Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Similar to other molecularly targeted agents, temsirolimus, an inhibitor of mammalian target of rapamycin, has shown promising activity in advanced renal cell carcinoma. However, only a subset of patients appears to derive significant tumor responses. In an effort to identify potential predictors of response to temsirolimus, tumor samples from a subset of patients within a randomized phase II trial of temsirolimus in advanced renal cell carcinoma were studied.. Paraffin-embedded tissue sections from patients who had received temsirolimus were immunostained with antibodies to carbonic anhydrase IX, phospho-S6, phospho-Akt (pAkt), and phosphotase and tensin homologue. Expression levels were correlated with objective response (partial response [PR], minor response [MR]) and clinical benefit (PR, MR, SD>or=4 cycles) to temsirolimus. In addition, von Hippel-Lindau (VHL) mutational analysis was performed and correlated with response.. Tissue specimens were obtained from 20 patients who were evaluable for both tumor response and staining for phospho-S6 and carbonic anhydrase IX. In addition, 19 specimens were evaluable for pAkt, and 18 for phosphotase and tensin homologue. VHL mutational analysis was performed on 16 samples. Five patients achieved an objective response (1 PR/4 MRs) to temsirolimus. There was a positive association of phospho-S6 expression (P=.02) and a trend toward positive expression of pAkt (P=.07) with response to temsirolimus. No patient without high expression of either phospho-S6 or pAkt experienced an objective tumor response. There was no correlation of carbonic anhydrase IX and phosphotase and tensin homologue expression or VHL status with response to temsirolimus.. These results suggest that phospho-S6 and pAkt expression are promising predictive biomarkers for response to temsirolimus that are worthy of further exploration for use in patient selection models for mammalian target of rapamycin inhibitors.

Topics: Antigens, Neoplasm; Biomarkers, Tumor; Carbonic Anhydrase IX; Carbonic Anhydrases; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Female; Humans; Immunoenzyme Techniques; Kidney Neoplasms; Male; Mutation; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases; Von Hippel-Lindau Tumor Suppressor Protein

Tuberous Sclerosis Complex (TSC) is an autosomal dominant hamartoma disorder with variable expression for which treatment options are limited. TSC is caused by a mutation in either the TSC1 or TSC2 genes, whose products, hamartin and tuberin, function as negative regulators in the highly-conserved mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin (also known as sirolimus), an mTOR inhibitor, has been shown to reduce disease severity in rodent models of TSC and is currently being evaluated in clinical trials in human populations. The cytokine interferon-gamma (IFN-gamma) is also a potential therapeutic agent for TSC. A high-expressing IFN-gamma allele has been associated with reduced disease severity in human TSC patients and it has been shown in mouse models that treatment with exogenous IFN-gamma reduces disease severity.. Here, we examine the effects of treating Tsc2+/- mice at different time points with a rapamycin analog (CCI-779) as a single agent or with a combination of CCI-779 and IFN-gamma. We observed that administering a short course of CCI-779 or CCI-779 plus IFN-gamma reduced the severity of kidney lesions if administered after such lesions develop. As long as treatment is given after lesions arise, altering the time period during which treatment was given did not significantly impact the effect of the treatment on disease severity. We did not observe a significant benefit of combination therapy relative to treatment with a rapamycin analog alone in Tsc2+/- mice. We also compared timing of treatment and two mTOR inhibitors (rapamycin and CCI-779) in nude mice bearing Tsc2-/- tumors.. Preventing the genesis of TSC-related kidney lesions in Tsc2+/- mice is not an effective treatment strategy; rather, the presence of growing tumors appears to be the most important factor when determining an appropriate treatment schedule. Treatment with rapamycin was more effective in reducing tumor growth and improving survival in nude mice bearing Tsc2-/- tumors and also resulted in higher rapamycin levels in blood, brain, and kidney tissue than treatment with an equal milligram dose of CCI-779. We anticipate these results will influence future preclinical and clinical trials for TSC.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Interferon-gamma; Kidney Diseases; Male; Mice; Mice, Nude; Sirolimus; Tissue Distribution; Tuberous Sclerosis

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Drug Costs; Drug Interactions; Humans; Infusions, Intravenous; Kidney Neoplasms; Neoplasm Staging; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Neovascularization, Pathologic; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Sirolimus

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Disease-Free Survival; Follow-Up Studies; Humans; Interferon-alpha; Kidney Neoplasms; Middle Aged; Neoplasm Staging; Orphan Drug Production; Sirolimus; United States; United States Food and Drug Administration

Acute lymphoblastic leukemia (ALL) in adult patients is often resistant to current therapy, making the development of novel therapeutic agents paramount. We investigated whether mTOR inhibitors (MTIs), a class of signal transduction inhibitors, would be effective in primary human ALL. Lymphoblasts from adult patients with precursor B ALL were cultured on bone marrow stroma and were treated with CCI-779, a second generation MTI. Treated cells showed a dramatic decrease in cell proliferation and an increase in apoptotic cells, compared to untreated cells. We also assessed the effect of CCI-779 in a NOD/SCID xenograft model. We treated a total of 68 mice generated from the same patient samples with CCI-779 after establishment of disease. Animals treated with CCI-779 showed a decrease in peripheral-blood blasts and in splenomegaly. In dramatic contrast, untreated animals continued to show expansion of human ALL. We performed immunoblots to validate the inhibition of the mTOR signaling intermediate phospho-S6 in human ALL, finding down-regulation of this target in xenografted human ALL exposed to CCI-779. We conclude that MTIs can inhibit the growth of adult human ALL and deserve close examination as therapeutic agents against a disease that is often not curable with current therapy.

Topics: Adult; Aged; Animals; Apoptosis; Burkitt Lymphoma; Cell Proliferation; Drug Evaluation, Preclinical; Enzyme Inhibitors; Female; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Tumor Cells, Cultured

Mammalian target of rapamycin (mTOR) is considered to be a major effector of cell growth and proliferation that controls protein synthesis through a large number of downstream targets. We investigated the expression of the phosphatidylinositol 3'-kinase (PI3K)/mTOR signaling pathway in human pancreatic cancer cells and tissues, and the in vivo antitumor effects of the mTOR inhibitor CCI-779 with/without gemcitabine in xenograft models of human pancreatic cancer. We found that the Akt, mTOR and p70 S6 kinase (S6K1) from the PI3K/mTOR signaling pathway were activated in all of the pancreatic cancer cell lines examined. When surgically resected tissue specimens of pancreatic ductal adenocarcinoma were examined, phosphorylation of Akt, mTOR and S6K1 was detected in 50, 55 and 65% of the specimens, respectively. Although CCI-779 had no additive or synergistic antiproliferative effect when combined with gemcitabine in vitro, it showed significant antitumor activity in the AsPC-1 subcutaneous xenograft model as both a single agent and in combination with gemictabine. Furthermore, in the Suit-2 peritoneal dissemination xenograft model, the combination of these 2 drugs achieved significantly better survival when compared with CCI-779 or gemcitabine alone. These results demonstrate promising activity of the mTOR inhibitor CCI-779 against human pancreatic cancer, and suggest that the inhibition of mTOR signaling can be exploited as a potentially tumor-selective therapeutic strategy.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Gemcitabine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinases; Signal Transduction; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Transplantation, Heterologous

Mammalian target of rapamycin (mTOR) inhibitors curtail cap-dependent translation. However, they can also induce post-translational modifications of proteins. We assessed both effects to understand the mechanism by which mTOR inhibitors like rapamycin sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Sensitization was achieved in multiple myeloma cells irrespective of their PTEN or p53 status, enhanced by activation of AKT, and associated with stimulation of both intrinsic and extrinsic pathways of apoptosis. The sensitizing effect was not due to post-translational modifications of the RAFTK kinase, Jun kinase, p38 mitogen-activated protein kinase, or BAD. Sensitization was also not associated with a rapamycin-mediated increase in glucocorticoid receptor reporter expression. However, when cap-dependent translation was prevented by transfection with a mutant 4E-BP1 construct, which is resistant to mTOR-induced phosphorylation, cells responded to dexamethasone with enhanced apoptosis, mirroring the effect of coexposure to rapamycin. Thus, sensitization is mediated by inhibition of cap-dependent translation. A high-throughput screening for translational efficiency identified several antiapoptotic proteins whose translation was inhibited by rapamycin. Immunoblot assay confirmed rapamycin-induced down-regulated expressions of XIAP, CIAP1, HSP-27, and BAG-3, which may play a role in the sensitization to apoptosis. Studies in a xenograft model showed synergistic in vivo antimyeloma effects when dexamethasone was combined with the mTOR inhibitor CCI-779. Synergistic effects were associated with an enhanced multiple myeloma cell apoptosis in vivo. This study supports the strategy of combining dexamethasone with mTOR inhibitors in multiple myeloma and identifies a mechanism by which the synergistic effect is achieved.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; bcl-Associated Death Protein; Carrier Proteins; Cell Cycle Proteins; Cell Line, Tumor; Dexamethasone; Drug Synergism; Focal Adhesion Kinase 2; Humans; MAP Kinase Kinase 4; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; p38 Mitogen-Activated Protein Kinases; Phosphoproteins; Protein Kinase Inhibitors; Protein Kinases; Receptors, Glucocorticoid; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases

Mammalian target of rapamycin (mTOR) is increasingly recognized as a master regulator of fundamental cellular functions, whose deregulation may underlie neoplastic transformation and progression. Hence, mTOR has recently emerged as a promising target for therapeutic anticancer interventions in several human tumors, including breast cancer. Here, we investigated the antiangiogenic potential of temsirolimus (also known as CCI-779), a novel mTOR inhibitor currently in clinical development for the treatment of breast cancer and other solid tumors. Consistent with previous reports, sensitivity to temsirolimus-mediated growth inhibition varied widely among different breast cancer cell lines and was primarily due to inhibition of proliferation with little, if any, effect on apoptosis induction. In the HER-2 gene-amplified breast cancer cell line BT474, temsirolimus inhibited vascular endothelial growth factor (VEGF) production in vitro under both normoxic and hypoxic conditions through inhibition of hypoxia-stimulated hypoxia-inducible factor (HIF)-1alpha expression and transcriptional activation. Interestingly, these effects were also observed in the MDA-MB-231 cell line, independent of its inherent sensitivity to the growth-inhibitory effects of temsirolimus. A central role for mTOR (and the critical regulator of cap-dependent protein translation, eIF4E) in the regulation of VEGF production by BT474 cells was further confirmed using a small interfering RNA approach to silence mTOR and eIF4E protein expression. In addition to its effect on HIF-1alpha-mediated VEGF production, temsirolimus also directly inhibited serum- and/or VEGF-driven endothelial cell proliferation and morphogenesis in vitro and vessel formation in a Matrigel assay in vivo. Overall, these results suggest that antiangiogenic effects may substantially contribute to the antitumor activity observed with temsirolimus in breast cancer.

Topics: Angiogenesis Inhibitors; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Humans; Neovascularization, Pathologic; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Agents; Central Nervous System Neoplasms; Combined Modality Therapy; Drug Therapy, Combination; ErbB Receptors; Gefitinib; Glioma; Humans; Indoles; Protein Kinase C; Protein Kinase Inhibitors; Protein Kinases; Quinazolines; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

Angiogenesis is one of the critical steps in tumor growth and metastasis. The goal of this study was to evaluate whether the antitumor activity of CCI-779 is related to antiangiogenic effects in vivo in tumors of mice bearing human rhabdomyosarcoma (RMS) xenografts. We now demonstrate that CCI-779 rapidly inhibits mTOR activity, as indicated by S6 reduction and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation in two xenograft models of RMS within 24 hours of treatment. Treatment with a single 20-mg/kg dose of CCI-779 suppressed S6 phosphorylation for more than 72 hours and 4E-BP1 phosphorylation for more than 96 hours. Based on these data, an intermittent treatment schedule (every 3 days for 30 days) was chosen and displayed a significant suppression of both tumor growth and mTOR signaling. Western blot analysis and immunohistochemical studies demonstrated that the antitumor activity of CCI-779 was associated with antiangiogenesis, as indicated by impaired levels of hypoxia-inducible factor-1alpha (Hif-1alpha) and vascular endothelial growth factor (VEGF) protein expression and by decreased microvessel density in Rh30 and RD xenografts. Together, these data suggest that CCI-779 inhibits human RMS xenograft growth by an antiangiogenic mechanism associated with the targeting of mTOR/Hif-1alpha/VEGF signaling.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, SCID; Neoplasm Transplantation; Neovascularization, Pathologic; Phosphorylation; Protein Kinases; Rhabdomyosarcoma; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The aims of this study were reviewing our experience regarding the pulmonary toxicity of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, discussing potential pathogenic mechanisms and proposing management strategies. Medical records and radiological reports of 22 patients treated with weekly doses of temsirolimus 25 mg were reviewed. Eight (36%) out of 22 patients developed pulmonary abnormalities compatible with drug-induced pneumonitis. Half were asymptomatic and in those with symptoms, dyspnea and dry cough were the most common. Radiologically two different patterns, ground glass opacities and lung parenchymal consolidation, were described. The management of this toxicity was variable, ranging from no intervention to discontinuation of the drug. In our experience temsirolimus may cause drug-induced pneumonitis at a higher incidence than that previously reported. The presentation and its severity are variable. The risk of developing this toxicity may be increased among subjects with abnormal pre-treatment pulmonary functions or history of lung disease.

Topics: Adult; Aged; Antineoplastic Agents; Endometrial Neoplasms; Female; Humans; Lung Diseases; Male; Middle Aged; Neuroectodermal Tumors; Sirolimus; Tomography, X-Ray Computed

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Indoles; Kidney Neoplasms; Lapatinib; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib

Tuberous sclerosis complex (TSC) is a familial tumor syndrome characterized by the development of hamartomas in the brain, heart, kidney, and skin. Disease-causing mutations in the TSC1 or TSC2 gene result in constitutive activation of the highly conserved mTOR signal transduction pathway, which regulates cell growth, proliferation, and metabolism. The mTOR inhibitor, rapamycin (sirolimus), reduces disease severity in rodent models of TSC, and is currently in phase II clinical trials. The cytokine interferon-gamma (IFN-gamma) is another potential therapeutic agent for TSC. A high-expressing IFN-gamma allele is associated with a lower frequency of kidney tumors in TSC patients, and treatment with exogenous IFN-gamma reduces the severity of TSC-related disease in mouse models. Here, we examine the effects of treating tumor-bearing nude mice with a combination of a rapamycin analog (CCI-779) and IFN-gamma. We observed that combination therapy was more effective than single agent therapy in reducing tumor growth and improving survival in this mouse model of TSC. Immunoblot and immunohistochemical analyses showed that tumors treated with CCI-779 plus IFN-gamma had decreased cell proliferation and increased cell death in comparison with untreated tumors or tumors treated with either agent alone. We also observed that CCI-779 resistance could develop with prolonged treatment. Taken together, our results show that targeting multiple cellular pathways is an effective strategy for treating TSC-related tumors, and underscore the importance of investigating combination therapy in future clinical trials for patients with TSC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Disease Models, Animal; Drug Therapy, Combination; Interferon-gamma; Mice; Mice, Knockout; Mice, Nude; Signal Transduction; Sirolimus; Survival Rate; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials. The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.

Topics: Animals; Antineoplastic Agents; Benzamides; Carcinoma; Deoxycytidine; Disease Models, Animal; Female; Gemcitabine; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Kinetics; Mice; Mice, Nude; Pancreatic Neoplasms; Predictive Value of Tests; Sirolimus; Transplantation, Heterologous; Xenograft Model Antitumor Assays

The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor-alpha (ERalpha) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxytamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ERalpha as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle; Cell Division; Cell Line, Tumor; Estrogen Receptor Modulators; Female; Genetic Markers; Humans; Indoles; Mice; Mice, Nude; Ovariectomy; Piperidines; Polymerase Chain Reaction; Restriction Mapping; Sirolimus; Thymectomy; Transfection

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indoles; Interferon-alpha; Kidney Neoplasms; Lapatinib; Multicenter Studies as Topic; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrroles; Quinazolines; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib; Treatment Outcome; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Lapatinib; Pyrroles; Quinazolines; Sirolimus; Sunitinib

Breast cancer is the most common malignancy and the second most common cause of cancer-related death in women. Endocrine therapy has been used for more than a century to treat advanced-stage breast cancer. The results obtained with the third-generation aromatase inhibitor letrozole demonstrated an actual improvement in patient outcome compared with tamoxifen. This benefit translates into disease-free survival improvement for adjuvant treatment and overall survival in patients with metastatic disease. The present clinical situation of hormonal therapy is stable; however, recently, new anticancer agents (temsirolimus and everolimus) that inhibit mammalian target of rapamycin protein kinase have been developed and seem to be very promising because of their synergistic activity with letrozole. The phase II study of a combination of temsirolimus or everolimus with letrozole demonstrated a better progression-free survival in the combination arm than in the letrozole alone arm. Consequently, the results of ongoing phase III studies are eagerly awaited.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Letrozole; Nitriles; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Triazoles

Tuberous sclerosis complex (TSC) is a familial tumor disorder for which there is no effective medical therapy. Disease-causing mutations in the TSC1 or TSC2 gene lead to increased mammalian target of rapamycin (mTOR) kinase activity in the conserved mTOR signaling pathway, which regulates nutrient uptake, cell growth, and protein translation. The normal function of TSC1 and TSC2 gene products is to form a complex that reduces mTOR kinase activity. Thus, mTOR kinase inhibition may be a useful targeted therapeutic approach. Elevated interferon-gamma (IFN-gamma) expression is associated with decreased severity of kidney tumors in TSC patients and mouse models; therefore, IFN-gamma also has therapeutic potential. We studied cohorts of Tsc2+/- mice and a novel mouse model of Tsc2-null tumors in order to evaluate the efficacy of targeted therapy for TSC. We found that treatment with either an mTOR kinase inhibitor (CCI-779, a rapamycin analog) or with IFN-gamma reduced the severity of TSC-related disease without significant toxicity. These results constitute definitive preclinical data that justify proceeding with clinical trials using these agents in selected patients with TSC and related disorders.

Topics: Animals; Cystadenoma; Disease Models, Animal; Drug Therapy, Combination; Hemangioma; Interferon-gamma; Kidney Neoplasms; Liver Neoplasms, Experimental; Mice; Mice, Knockout; Mice, Nude; Phosphorylation; Protein Kinases; Repressor Proteins; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Topics: Androgen Receptor Antagonists; Androgens; Antineoplastic Agents; Biomarkers, Tumor; Drug Resistance, Neoplasm; Gefitinib; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Male; Phosphoric Monoester Hydrolases; Predictive Value of Tests; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Kinases; PTEN Phosphohydrolase; Quinazolines; Receptors, Androgen; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Up-Regulation

Given their accessibility, surrogate tissues, such as peripheral blood mononuclear cells (PBMC), may provide potential predictive biomarkers in clinical pharmacogenomic studies. In leukemias and lymphomas, the prognostic value of peripheral blast expression profiles is clear; however, it is unclear whether circulating mononuclear cells of patients with solid tumors might yield profiles with similar prognostic associations.. In this study, we evaluated the association of expression profiles in PBMCs with clinical outcomes in patients with advanced renal cell cancer. Transcriptional patterns in PBMCs of 45 renal cell cancer patients were compared with clinical outcome data at the conclusion of a phase II study of the mTOR kinase inhibitor CCI-779 to determine whether pretreatment transcriptional patterns in PBMCs were correlated with eventual patient outcomes.. Unsupervised hierarchical clustering of the PBMC profiles using all expressed genes identified clusters of patients with significant differences in survival. Cox proportional hazards modeling showed that the expression levels of many PBMC transcripts were predictors for the patient outcomes of time to progression and overall survival (time to death). Supervised class prediction approaches identified multivariate expression patterns in PBMCs capable of assigning favorable outcomes of time to death and time to progression in a test set of renal cancer patients, with overall performance accuracies of 72% and 85%, respectively.. The present study provides the first example of gene expression profiling in peripheral blood, a clinically accessible surrogate tissue, for identifying patterns of gene expression associated with higher likelihoods of positive outcome in patients with a solid tumor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Cluster Analysis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Leukocytes, Mononuclear; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Prognosis; Sirolimus; Survival Analysis; Transcription, Genetic; Treatment Outcome

Osteosarcoma is the most frequent primary malignant tumor of bone with a high propensity for metastasis. We have previously showed that ezrin expression is necessary for metastatic behavior in a murine model of osteosarcoma (K7M2). In this study, we found that a mechanism of ezrin-related metastatic behavior is linked to an Akt-dependent mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (S6K1)/eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) pathway. Suppression of ezrin expression either by antisense transfection or by small interfering RNAs or disruption of ezrin function by transfection of a dominant-negative ezrin-T567A mutant led to decreased expression and decreased phosphorylation of both S6K1 and 4E-BP1. Proteosomal inhibition by MG132 reversed antisense-mediated decrease of S6K1 and 4E-BP1 protein expression, but failed to affect the effect of ezrin on phosphorylation of S6K1 and 4E-BP1. Blockade of the mTOR pathway with rapamycin or its analog, cell cycle inhibitor-779 led to significant inhibition of experimental lung metastasis in vivo. These results suggest that blocking the mTOR/S6K1/4E-BP1 pathway may be an appropriate target for strategies to reduce tumor cell metastasis.

Topics: Adaptor Proteins, Signal Transducing; Animals; Bone Neoplasms; Carrier Proteins; Cell Cycle Proteins; Cytoskeletal Proteins; Eukaryotic Initiation Factors; Female; Mice; Mice, SCID; Osteosarcoma; Phosphoproteins; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Antisense; RNA, Small Interfering; Sirolimus; Transfection

Selective inhibition of repopulation of surviving tumor cells between courses of chemotherapy might improve the outcome of treatment. A potential target for inhibiting repopulation is the mammalian target of rapamycin pathway; PTEN-negative tumor cells are particularly sensitive to inhibition of this pathway. Here we study the rapamycin analogue CCI-779, alone or with chemotherapy, as an inhibitor of proliferation of the human prostate cancer cell lines PC-3 and DU145. The PTEN and phospho-Akt/PKB status and the effect of CCI-779 on phosphorylation of ribosomal protein S6 were evaluated by immunostaining and/or Western blotting. Expression of phospho-Akt/PKB in PTEN mutant PC-3 cells and xenografts was higher than in PTEN wild-type DU145 cells. Phosphorylation of S6 was inhibited by CCI-779 in both cell lines. Cultured cells were treated weekly with mitoxantrone or docetaxel for two cycles, and CCI-779 or vehicle was given between courses. Growth and clonogenic survival of both cell lines were inhibited in a dose-dependent manner by CCI-779, but there were minimal effects when CCI-779 was given between courses of chemotherapy. CCI-779 inhibited the growth of xenografts derived from both cell lines with greater effects against PC-3 than DU145 tumors. CCI-779 caused mild myelosuppression. The activity of mitoxantrone or docetaxel was limited, but CCI-779 given between courses of chemotherapy increased growth delay of PC-3 xenografts. Our results suggest that repopulation of PTEN-negative cancer cells between courses of chemotherapy might be inhibited by CCI-779.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Growth Processes; Cell Line, Tumor; Cell Proliferation; Docetaxel; Drug Synergism; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mitoxantrone; Phosphoric Monoester Hydrolases; Phosphorylation; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Ribosomal Protein S6; Sirolimus; Taxoids; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays

The serine/threonine kinase AKT and its downstream mediator mammalian target of rapamycin (mTOR) are activated in lung adenocarcinoma, and clinical trials are under way to test whether inhibition of mTOR is useful in treating lung cancer. Here, we report that mTOR inhibition blocked malignant progression in K-ras(LA1) mice, which undergo somatic activation of the K-ras oncogene and display morphologic changes in alveolar epithelial cells that recapitulate those of precursors of human lung adenocarcinoma. Levels of phospho-S6(Ser236/235), a downstream mediator of mTOR, increased with malignant progression (normal alveolar epithelial cells to adenocarcinoma) in K-ras(LA1) mice and in patients with lung adenocarcinoma. Atypical alveolar hyperplasia, an early neoplastic change, was prominently associated with macrophages and expressed high levels of phospho-S6(Ser236/235). mTOR inhibition in K-ras(LA1) mice by treatment with the rapamycin analogue CCI-779 reduced the size and number of early epithelial neoplastic lesions (atypical alveolar hyperplasia and adenomas) and induced apoptosis of intraepithelial macrophages. LKR-13, a lung adenocarcinoma cell line derived from K-ras(LA1) mice, was resistant to treatment with CCI-779 in vitro. However, LKR-13 cells grown as syngeneic tumors recruited macrophages, and those tumors regressed in response to treatment with CCI-779. Lastly, conditioned medium from primary cultures of alveolar macrophages stimulated the proliferation of LKR-13 cells. These findings provide evidence that the expansion of lung adenocarcinoma precursors induced by oncogenic K-ras requires mTOR-dependent signaling and that host factors derived from macrophages play a critical role in adenocarcinoma progression.

Topics: Adenocarcinoma; Adenoma; Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Disease Progression; Enzyme Activation; Genes, ras; Hyperplasia; Lung Neoplasms; Macrophages, Alveolar; Mice; Mutation; Precancerous Conditions; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pulmonary Alveoli; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases

We present immunohistochemical evidence that the mTOR/p70s6k pathway is activated in pancreatic tumors and show that the mTOR inhibitor and rapamycin analog CCI-779 potently suppresses the proliferation of pancreatic cancer cells. Consistent with a recent study, CCI-779 increased c-Jun phosphorylation (Ser63) in a dose- and time-dependent manner, and induced apoptosis in p53-defective BxPC-3 cells. In contrast to the study, however, we observed that CCI-779 concomitantly increased c-Jun protein levels and that its ability to induce apoptosis might not require the activated c-Jun. Furthermore, CCI-779 neither induced c-Jun phosphorylation in other p53-defective pancreatic cancer cells (MiaPaCa-2) nor inhibited their proliferation. c-Jun, in fact, appeared to be partly responsible for the resistance of MiaPaCa-2 cells to CCI-779. Together, these results indicate a complex role for c-Jun in cellular responses to CCI-779 and provide an important basis for investigating CCI-779 further as a potential therapeutic agent for pancreatic tumors.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Immunohistochemistry; Mutation; Pancreatic Neoplasms; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-jun; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Pancreatic cancer is still a malignant disease with a poor prognosis. Except for surgery, no curative treatment has been found, albeit large research efforts. Agents, such as growth factors and hormones, have been shown to stimulate cell proliferation, whereas their receptor antagonists have been less efficient to inhibit cell proliferation. The aim of this study was to examine the effect of inhibitors of the intracellular signal cascades on pancreatic cancer cell number.. A cell line was developed from a patient with pancreatic cancer and subcloned to three generations. The four cell lines were grown in serum-free medium. The effects of PD98059, LY294002, rapamycin and its analogue CCI-779 were tested in dose-response experiments. The chemotherapeutic agent gemcitabine, with or without combination of the other potential inhibitor drugs in different concentrations, was also examined. The cell number was evaluated with the XTT method.. PD98059 reduced the cell number in all the cell lines tested. At a concentration of 10(-4) M the cell number was reduced by 50-90%. LY294002 reduced the cell number by 40-50% at the same concentration. Two of four cell lines had their cell number reduced by CCI-779 by 60%, whereas the other two cell lines were reduced by 30%. Rapamycin or gemcitabine alone had no or only moderate effect on single cell lines. Different combinations of CCI-779 and gemcitabine led to reduction of the cell number by about 50% in concentrations up to 10(-7) M.. Inhibitors of the intracellular signal cascades can reduce the cell number of human pancreatic cancer cell lines. Inhibitors of the mitogen-activated protein kinase downstream signalling cascades seem to be more efficient than the other inhibitors. PD98059 and CCI-779, in combination with gemcitabine, could be worth studying in clinical conditions.

Topics: Antibiotics, Antineoplastic; Carcinoma, Pancreatic Ductal; Cell Division; Chromones; Culture Media, Serum-Free; Enzyme Inhibitors; Flavonoids; Humans; Morpholines; Pancreatic Neoplasms; Signal Transduction; Sirolimus; Tumor Cells, Cultured

Tauroursodeoxycholic acid (TUDCA) is a cytoprotective bile acid frequently prescribed to patients with cholestatic diseases. Several mechanisms of action have been investigated, but the possibility that cyclic adenosine monophosphate responsive element binding protein (CREB), a transcription factor promoting cell survival, mediates TUDCA's protective effects has not been considered. We examined whether TUDCA activates CREB and whether this activation can protect biliary epithelial cells. Cholangiocytes were stressed by exposure to CCI-779, which inhibits signaling though the kinase mTOR (mammalian target of rapamycin), resulting in cell cycle arrest and apoptosis. Incubation of normal rat cholangiocytes (NRC) cells, with TUDCA resulted in phosphorylation of CREB (Western blotting analysis) and activation of CREB transcription activity (luciferase reporter assay). Inhibition of calcium signals and inhibition of protein kinase C prevented the TUDCA-induced activation of CREB. CCI-779 decreased the viability of rat cholangiocytes in a dose-dependent manner (MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay). TUDCA protected against CCI-779 cytotoxicity. A dominant negative form of CREB was stably transduced in NRC cells (NRC-M1). TUDCA protection was decreased in NRC-M1. While CCI-779 induced apoptosis in NRC cells as determined by caspase 3 activity, TUDCA attenuated CCI-779-induced apoptosis, an effect absent in NRC-M1. Finally, CCI-779 blocked proliferation of both NRC and NRC-M1 (thymidine incorporation) and this was unaffected by TUDCA. In conclusion, TUDCA activates CREB in cholangiocytes, reducing the apoptotic effect of CCI-779. These findings suggest a novel cytoprotective mechanism for this bile acid.

Topics: Animals; Apoptosis; Bile Ducts; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclic AMP Response Element-Binding Protein; Cytoprotection; Phosphorylation; Protein Kinases; Rats; Sirolimus; Taurochenodeoxycholic Acid; TOR Serine-Threonine Kinases; Transcription, Genetic

Combined activation of Ras and AKT leads to the formation of astrocytic glioblastoma multiforme (GBM) in mice. In human GBMs, AKT is not mutated but is activated in approximately 70% of these tumors, in association with loss of PTEN and/or activation of receptor tyrosine kinases. Mechanistic justification for the therapeutic blockade of targets downstream of AKT, such as mTOR, in these cancers requires demonstration that the oncogenic effect of PTEN loss is through elevated AKT activity. We demonstrate here that loss of Pten is similar to AKT activation in the context of glioma formation in mice. We further delineate the role of mTOR activity downstream of AKT in the maintenance of AKT+KRas-induced GBMs. Blockade of mTOR results in regional apoptosis in these tumors and conversion in the character of surviving tumor cells from astrocytoma to oligodendroglioma. These data suggest that mTOR activity is required for the survival of some cells within these GBMs, and mTOR appears required for the maintenance of astrocytic character in the surviving cells. Furthermore, our study provides the first example of conversion between two distinct tumor types usually thought of as belonging to specific lineages, and provides evidence for signal transduction-mediated transdifferentiation between glioma subtypes.

Topics: Animals; Apoptosis; Blotting, Western; Brain; Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Survival; Cells, Cultured; Enzyme Activation; Exons; Glioblastoma; Green Fluorescent Proteins; Immunohistochemistry; In Situ Nick-End Labeling; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Genetic; Mutation; Neurons; Phosphatidylinositol 3-Kinases; Phosphoric Monoester Hydrolases; Plasmids; Polymerase Chain Reaction; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; Stem Cells; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1 messenger RNA. This study tested whether temsirolimus (previously known as CCI-779), an inhibitor of the mammalian target of rapamycin kinase that regulates cyclin D1 translation, could produce tumor responses in patients with MCL.. Patients with relapsed or refractory MCL were eligible to receive temsirolimus 250 mg intravenously every week as a single agent. Patients with a tumor response after six cycles were eligible to continue drug for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance.. Thirty-five patients were enrolled and were assessable for toxicity; one patient had MCL by histology but was cyclin D1 negative and was ineligible for efficacy. The median age was 70 years (range, 38 to 89 years), 91% were stage 4, and 69% had two or more extranodal sites. Patients had received a median of three prior therapies (range, one to 11), and 54% were refractory to the last treatment. The overall response rate was 38% (13 of 34 patients; 90% CI, 24% to 54%) with one complete response (3%) and 12 partial responses (35%). The median time-to-progression in all patients was 6.5 months (95% CI, 2.9 to 8.3 months), and the duration of response for the 13 responders was 6.9 months (95% CI, 5.2 to 12.4 months). Hematologic toxicities were the most common, with 71% (25 of 35 patients) having grade 3 and 11% (four of 35 patients) having grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reductions but was of short duration, typically resolving within 1 week.. Single-agent temsirolimus has substantial antitumor activity in relapsed MCL. This study demonstrates that agents that selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. Further studies of this agent in MCL and other lymphoid malignancies are warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cyclin D1; Disease Progression; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Ribosomal Protein S6 Kinases; Salvage Therapy; Sirolimus; Time Factors; Treatment Outcome; Tumor Cells, Cultured

Cisplatin resistance is complex and involves several different mechanisms. Employing cDNA microarray analysis, we have found that cisplatin resistant cells share the common characteristic of increase in ribosomal proteins and elongation factors. We hypothesize that in order to survive cisplatin treatment, cells have to synthesize DNA repair proteins, antiapoptotic proteins and growth-stimulating proteins. Thus, by blocking the translation of these proteins, one should be able to restore cisplatin sensitivity. We have studied the role of CCI-779, an ester analog of rapamycin which is known to inhibit translation by disabling mTOR, in restoring cisplatin sensitivity in a panel of cisplatin resistant cell lines. We have also determined the role of CCI-779 in P-gp1 and MRP1 mediated resistance.. Our data show that CCI-779 possess antiproliferative effects in both cisplatin sensitive and resistant cell lines, but shows no effect in P-gp1 and MRP1 overexpressing cell lines. Importantly, CCI-779 at 10 ng/ml (less that 10% of the growth inhibitory effect) can increase the growth inhibition of cisplatin by 2.5-6 fold. Moreover, CCI-779 also enhances the apoptotic effect of cisplatin in cisplatin resistant cell lines. In these resistant cells, adding CCI-779 decreases the amount of 4E-BP phosphorylation and p-70S6 kinase phosphorylation as well as lower the amount of elongation factor while cisplatin alone has no effect. However, CCI-779 can only reverse P-gp mediated drug resistance at a higher dose(1 ug/ml).. We conclude that CCI-779 is able to restore cisplatin sensitivity in small cell lung cancer cell lines selected for cisplatin resistance as well as cell lines derived from patients who failed cisplatin. These findings can be further explored for future clinical use. On the other hand, CCI-779 at achievable clinical concentration, has no growth inhibitory effect in P-gp1 or MRP1 overexpressing cells. Furthermore, CCI-779 also appears to be a weak MDR1 reversal agent. Thus, it is not a candidate to use in MDR1 or MRP1 overexpressing cells.

Topics: Adaptor Proteins, Signal Transducing; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Proliferation; Cisplatin; Doxorubicin; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases

To assess the efficacy of Mytrolimus (CCI-779), a derivative of rapamycin, eluting stents in preventing restenosis in the porcine model.. The bare stents (n = 10), stents coated with polyolefin (n = 10) or stents coated with Mytrolimus (160 microg/18 mm) in polyolefin (n = 8) were implanted in left anterior descending coronary arteries or right coronary artery of mini-swine. Coronary angiography was performed after 4 weeks then the animals were sacrificed. The cross sections of the stented coronary arteries were analyzed, the injury score, luminal area, neointimal thickness above the struts and between the struts of stents, neointimal area and percentage of restenosis were measured.. The mean injury scores and luminal area were similar in three groups. There was no difference in above-stated items between the polyolefin coating stent and bare mental stent. To compare Mytrolimus-eluting stent with bare-stent, neointimal thickness above the struts [(0.18 +/- 0.08) mm vs (0.33 +/- 0.25) mm, P < 0.05] and between the struts [(0.14 +/- 0.05) mm vs (0.28 +/- 0.23) mm, P < 0.05] and neointimal area [(1.09 +/- 0.24) mm(2) vs (2.44 +/- 1.59) mm(2), P < 0.05] were significantly decreased in the Mytrolimus-eluting stent group than in bare mental stent group. Compared with bare-stent, the Mytrolimus eluting stent was associated with a 55.33% reduction in neointimal area. No restenosis developed in the Mytrolimus group.. The Mytrolimus-eluting stents can effectively inhibit the neointimal hyperplasia in stented areas of coronary arteries 4 weeks after stent implantation in porcine model.

Topics: Animals; Blood Vessel Prosthesis Implantation; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Sirolimus; Swine

A lipase-catalyzed acylation of the immunosuppressant rapamycin with complete regioselectivity is described. The method was successfully applied to the synthesis of 42-hemiesters and temsirolimus (CCI-779), an investigational oncology drug.[reaction: see text]

Topics: Antibiotics, Antineoplastic; Catalysis; Esterification; Lipase; Molecular Structure; Sirolimus; Stereoisomerism

PTEN is a tumor suppressor gene whose loss of function is observed in approximately 40-50% of human cancers. Although insulin-like growth factor binding protein-2 (IGFBP-2) was classically described as a growth inhibitor, multiple recent reports have shown an association of overexpression and/or high serum levels of IGFBP-2 with poor prognosis of several malignancies, including gliomas. Using an inducible PTEN expression system in the PTEN-null glioma cell line U251, we demonstrate that PTEN-induction is associated with reduced proliferation, increased apoptosis, and a substantial reduction of the high levels of IGFBP-2 expression. The PTEN-induced decrease in IGFBP-2 expression could be mimicked with the PI3-kinase inhibitor LY294002, indicating that the lipid phosphatase activity of PTEN is responsible for the observed effect. However, the rapamycin analog CCI-779 did not affect IGFBP-2 expression, suggesting that the PTEN-induced decrease in IGFBP-2 expression is not attributable to decreased mTOR signalling. Recombinant human IGFBP-2 was unable to rescue U251-PTEN cells from the antiproliferative effects of PTEN, and IGFBP-2 siRNA did not affect the IGF-dependent or -independent growth of this cell line. These results suggest that the clinical data linking IGFBP-2 expression to poor prognosis may arise, at least in part, because high levels of IGFBP-2 expression correlate with loss of function of PTEN, which is well known to lead to aggressive behavior of gliomas. Our results motivate translational research regarding the relationship between IGFBP-2 expression and loss of function of PTEN.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Chromones; Enzyme Induction; Gene Expression Regulation, Neoplastic; Glioma; Humans; Insulin-Like Growth Factor Binding Protein 2; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; PTEN Phosphohydrolase; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases

Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin and CCI-779, have shown preclinical potential as therapy for multiple myeloma. By inhibiting expression of cell cycle proteins, these agents induce G1 arrest. However, by also inhibiting an mTOR-dependent serine phosphorylation of insulin receptor substrate-1 (IRS-1), they may enhance insulin-like growth factor-I (IGF-I) signaling and downstream phosphatidylinositol 3-kinase (PI3K)/AKT activation. This may be a particular problem in multiple myeloma where IGF-I-induced activation of AKT is an important antiapoptotic cascade. We, therefore, studied AKT activation in multiple myeloma cells treated with mTOR inhibitors. Rapamycin enhanced basal AKT activity, AKT phosphorylation, and PI3K activity in multiple myeloma cells and prolonged activation of AKT induced by exogenous IGF-I. CCI-779, used in a xenograft model, also resulted in multiple myeloma cell AKT activation in vivo. Blockade of IGF-I receptor function prevented rapamycin's activation of AKT. Furthermore, rapamycin prevented serine phosphorylation of IRS-1, enhanced IRS-1 association with IGF-I receptors, and prevented IRS-1 degradation. Although similarly blocking IRS-1 degradation, proteasome inhibitors did not activate AKT. Thus, mTOR inhibitors activate PI3-K/AKT in multiple myeloma cells; activation depends on basal IGF-R signaling; and enhanced IRS-1/IGF-I receptor interactions secondary to inhibited IRS-1 serine phosphorylation may play a role in activation of the cascade. In cotreatment experiments, rapamycin inhibited myeloma cell apoptosis induced by PS-341. These results provide a caveat for future use of mTOR inhibitors in myeloma patients if they are to be combined with apoptosis-inducing agents.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Enzyme Activation; Humans; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I; Mice; Mice, SCID; Multiple Myeloma; Phosphatidylinositol 3-Kinases; Phosphoproteins; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Pyrazines; Receptor, IGF Type 1; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Prior work demonstrates that AKT activity regulates sensitivity of cells to G(1) arrest induced by mammalian target of rapamycin (mTOR) inhibitors such as rapamycin and CCI-779. To investigate this, a novel high-throughput microarray polysome analysis was performed to identify genes whose mRNA translational efficiency was differentially affected following mTOR inhibition. The analysis also allowed the assessment of steady-state transcript levels. We identified two transcripts, cyclin D1 and c-myc, which exhibited differential expression in an AKT-dependent manner: High levels of activated AKT resulted in rapamycin-induced down-regulation of expression, whereas low levels resulted in up-regulation of expression. To ectopically express these proteins we exploited the finding that the p27(kip1) mRNA was efficiently translated in the face of mTOR inhibition irrespective of AKT activity. Thus, the p27(kip1) 5'-untranslated region was fused to the cyclin D1 and c-myc coding regions and these constructs were expressed in cells. In transfected cells, expression of cyclin D1 or c-myc was not decreased by rapamycin. Most importantly, this completely converted sensitive cells to a phenotype resistant to G(1) arrest. Furthermore, the AKT-dependent differential expression patterns of these two genes was also observed in a mouse xenograft model following in vivo treatment with CCI-779. These results identify two critical downstream molecular targets whose expression is regulated by AKT activity and whose down-regulation is required for rapamycin/CCI-779 sensitivity.

Topics: Cell Line; Cyclin D1; G1 Phase; Gene Expression Regulation; Genes, myc; Humans; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Humans; Research Design; Sirolimus

In vitro studies indicate the therapeutic potential of mTOR inhibitors in treating multiple myeloma. To provide further support for this potential, we used the rapamycin analog CCI-779 in a myeloma xenograft model. CCI-779, given as 10 intraperitoneal injections, induced significant dose-dependent, antitumor responses against subcutaneous growth of 8226, OPM-2, and U266 cell lines. Effective doses of CCI-779 were associated with modest toxicity, inducing only transient thrombocytopenia and leukopenia. Immunohistochemical studies demonstrated the antitumor responses were associated with inhibited proliferation and angiogenesis, induction of apoptosis, and reduction in tumor cell size. Although CCI-779-mediated inhibition of the p70 mTOR substrate was equal in 8226 and OPM-2 tumor nodules, OPM-2 tumor growth was considerably more sensitive to inhibition of proliferation, angiogenesis, and induction of apoptosis. Furthermore, the OPM-2 tumors from treated mice were more likely to show down-regulated expression of cyclin D1 and c-myc and up-regulated p27 expression. Because earlier work suggested heightened AKT activity in OPM-2 tumors might induce hypersensitivity to mTOR inhibition, we directly tested this by stably transfecting a constitutively active AKT allele into U266 cells. The in vivo growth of the latter cells was remarkably more sensitive to CCI-779 than the growth of control U266 cells.

Topics: Animals; Cell Division; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Quinazolines; Sirolimus

The Akt kinase is a serine/threonine protein kinase that has been implicated in mediating a variety of biological responses. Studies show that high Akt activity in breast carcinoma is associated with a poor pathophenotype, as well as hormone and chemotherapy resistance. Additionally, high Akt activity is associated with other features of poor prognosis. Thus, a chemotherapeutic agent directed specifically toward tumors with high Akt activity could prove extremely potent in treating those breast tumors with the most aggressive phenotypes. Several studies have demonstrated that rapamycin, which inhibits mammalian target of rapamycin (mTOR), a downstream target of Akt, sensitizes certain resistant cancer cells to chemotherapeutic agents. This study evaluated the efficacy of mTOR inhibition in the treatment of tamoxifen-resistant breast carcinoma characterized by high Akt activity. We found that MCF-7 breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions and are resistant to the growth inhibitory effects of tamoxifen, both in vitro as well as in vivo in xenograft models. Cotreatment with the mTOR inhibitor rapamycin in vitro, or the ester of rapamycin, CCI-779 (Wyeth) in vivo, inhibited mTOR activity and restored sensitivity to tamoxifen, suggesting that Akt-induced tamoxifen resistance is mediated in part by signaling through the mTOR pathway. Although the mechanism underlying the synergism remains to be understood, the results were associated with rapamycin's ability to block transcriptional activity mediated by estrogen receptor alpha, as assessed by reporter gene assays with estrogen-responsive element luciferase. These data corroborate prior findings indicating that Akt activation induces resistance to tamoxifen in breast cancer cells. Importantly, these data indicate a novel mechanism for tamoxifen resistance and suggest that blockage of the phosphatidylinositol 3'-kinase/Akt signaling pathway by mTOR inhibition effectively restores the susceptibility of these cells to tamoxifen. These data may have implication for future clinical studies of mTOR inhibition in breast carcinoma.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases; Promoter Regions, Genetic; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptors, Estrogen; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Tamoxifen; TOR Serine-Threonine Kinases; Transcription, Genetic; Transplantation, Heterologous; Tumor Cells, Cultured

Topics: Acetyltransferases; Apoptosis; Cell Hypoxia; Everolimus; Histone Acetyltransferases; Neoplasms; Neovascularization, Pathologic; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Sirolimus

CCI-779 is an ester of rapamycin and inhibitor of mammalian target of rapamycin (mTOR) currently in Phase II clinical development for the treatment of patients with cancer. CCI-779 interacts with mTOR and inhibits its kinase activity, resulting in inhibition of the mTOR-regulated translational controllers p70(s6) kinase and 4E-BP1. Ultimately, CCI-779 decreases the translation of mRNAs involved in the control of the cell cycle, resulting in cell cycle arrest. The objective of this study was to develop a method to determine the pharmacodynamic effects of CCI-779 suitable for use in clinical trials. Exposure of Raji lymphoblastoid cells to increasing concentrations of rapamycin resulted in a linear concentration-dependent inhibition of p70(s6) kinase activity, suggesting that p70(s6) kinase activity could be an appropriate marker for mTOR-interacting agents. In subsequent experiments, treatment of nude mice bearing the CCI-779 susceptible breast cancer cell line MDA-468 with a single dose of 10 mg/kg CCI-779 resulted in a >80% inhibition of p70(s6) kinase activity in peripheral blood mononuclear cells (PBMCs) 72 h after treatment. Importantly, the degree of p70(s6) kinase inhibition was identical in PBMCs and simultaneously collected tumor tissue, suggesting that the PBMCs are an adequate surrogate tissue for p70(s6) kinase activity in vivo. The intrasubject coefficient of variation of p70(s6) kinase activity measured in PBMCs collected from five healthy volunteers on days 1, 4, and 8 was 14%, indicating that p70(s6) kinase activity in PBMCs remains relatively stable over time. Finally, p70(s6) kinase activity was measured in PBMCs from nine patients with renal cell cancer treated with a single dose of 25, 75, or 250 mg of CCI-779 i.v. (three patients each). PBMCs were collected on days 2, 4, and 8 after CCI-779 treatment. In this small data set, eight of the nine patients had evidence of p70(s6) kinase activity inhibition after treatment that was independent of the administered dose. There was a significant linear association between time to disease progression and inhibition of p70(s6) kinase activity 24 h after treatment. In conclusion, these results indicate that the pharmacodynamic effects of CCI-779 can be determined using a p70(s6) kinase assay in PBMCs. This assay is currently being incorporated in Phase I and II studies with CCI-779 to determine its relationship with dose and plasma concentration of the agent and its value as a predictor of treatme

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Cell Cycle; Cell Line, Tumor; Clinical Trials as Topic; Disease Progression; Dose-Response Relationship, Drug; Female; Humans; Immunoblotting; Kidney Neoplasms; Leukocytes, Mononuclear; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

The mechanisms that regulate mammalian cell size during development and homeostatic maintenance are poorly understood. The tumor suppressor Pten is required for correct maintenance of mammalian neuronal soma size. Selective inactivation of Pten in postnatal granule neurons of the cerebellum and dentate gyrus in mouse causes cell-autonomous hypertrophy as well as more complex phenotypes, including progressive macrocephaly, seizures, and premature death. To determine the contribution of mTor signaling to Pten-mediated growth regulation in the mammalian nervous system, we treated Pten conditional knockout mice with CCI-779, a specific mTor inhibitor. mTor inhibition decreased the seizure frequency and death rate in Pten mutant mice, prevented the increase in Pten-deficient neuronal soma size in young mice, and reversed neuronal soma enlargement in adult mice. mTor inhibition did not decrease the size of wild-type adult neurons. Thus, mTor is required for neuronal hypertrophy downstream of Pten deficiency, but is not required for maintenance of normal neuronal soma size. mTOR inhibitors may be useful therapeutic agents for diseases in brain resulting from PTEN deficiency such as Lhermitte-Duclos disease or glioblastoma multiforme.

Topics: Animals; Brain; Cell Division; Cerebellum; Dentate Gyrus; Genes, Tumor Suppressor; Hypertrophy; Mice; Mice, Knockout; Mice, Transgenic; Neurons; Phosphoric Monoester Hydrolases; Protein Kinase Inhibitors; Protein Kinases; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

Recent work identifies the AKT kinase as a potential mediator of tumor expansion in multiple myeloma. The finding of PTEN mutations in several myeloma cell lines suggests that loss of PTEN function may be one mechanism by which AKT activity is increased in this disease. Because PTEN-deficient myeloma cells may have up-regulated activity of the mammalian target of rapamycin (mTOR), downstream of AKT, they may be particularly sensitive to mTOR inhibition. To test this hypothesis, we challenged myeloma cell lines with CCI-779, a newly developed analogue of rapamycin and an efficient inhibitor of mTOR. Three of four PTEN-deficient cell lines with constitutively active AKT were remarkably sensitive to cytoreduction and G(1) arrest induced by CCI-779 with ID(50) concentrations of <1 nM. In contrast, myeloma cells expressing wild-type PTEN were >1000-fold more resistant. Acute expression of a constitutively active AKT gene in CCI-779-resistant myeloma cells containing wild-type PTEN and quiescent AKT did not convert them to the CCI-779-sensitive phenotype. Conversely, expression of wild-type PTEN in CCI-779-sensitive, PTEN-deficient myeloma cells did not induce resistance. Differential sensitivity did not appear to be due to differences in the ability of CCI-779 to inhibit mTOR and induce dephosphorylation of p70S6kinase or 4E-BP1. However, CCI-779 inhibited expression of c-myc in CCI-sensitive PTEN-null myeloma cells but had no effect on expression in CCI-resistant cells. In contrast, cyclin D1 expression was not altered in either sensitive or resistant cells. These results indicate that PTEN-deficient myeloma cells are remarkably sensitive to mTOR inhibition. Although the results of transfection studies suggest that the level of PTEN and AKT function per se does not regulate sensitivity, PTEN/AKT status may be a good predictive marker of sensitivity.

Topics: Adaptor Proteins, Signal Transducing; Antibiotics, Antineoplastic; Carrier Proteins; Cell Cycle Proteins; Cyclin D1; Enzyme Activation; Humans; Multiple Myeloma; Mutation; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; PTEN Phosphohydrolase; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

Topics: Astrocytoma; Brain Neoplasms; Carmustine; Dexamethasone; Diagnosis, Differential; Frontal Lobe; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phenytoin; Piloerection; Seizures; Sirolimus; Taste Disorders; Temporal Lobe

Topics: Animals; Antineoplastic Agents; Benzamides; Benzoquinones; Cell Cycle Proteins; DNA-Binding Proteins; E2F Transcription Factors; Gefitinib; Genes, Tumor Suppressor; HSP90 Heat-Shock Proteins; Humans; Imatinib Mesylate; Indoles; Lactams, Macrocyclic; Mutation; Neoplasms; Phosphoric Monoester Hydrolases; Piperazines; PTEN Phosphohydrolase; Pyrimidines; Pyrroles; Quinazolines; Rifabutin; Signal Transduction; Sirolimus; Transcription Factors; Tumor Suppressor Proteins

We examined the cytotoxicity of the immunosuppressant agent rapamycin and its analogue CCI-779 in human brain tumor cell lines in vitro and in vivo as single agents and in combination with standard chemotherapeutic drugs. In the rapamycin-sensitive PNET/MB cell line DAOY, rapamycin exhibited additive cytotoxicity with cisplatin and with camptothecin. In vivo, CCI-779 delayed DAOY xenograft growth by 160% after 1 week and 240% after 2 weeks of systemic treatment, compared with controls. Single high-dose treatment induced 37% regression of tumor solume. Growth inhibition of DAOY xenografts was 1.3 times greater after simultaneous treatment with CCI-779 and cisplatin than after cisplatin alone. Interestingly, CCI-779 also produced growth inhibition of xenografts derived from U251 malignant glioma cells, a human cell line resistant to rapamycin in vitro. These studies suggest that the rapamycin analogue CCI-779 is an important new agent to investigate in the treatment of human brain tumors, particularly PNET/MB.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Camptothecin; Cell Division; Cisplatin; Drug Synergism; Female; Glioma; Growth Inhibitors; Humans; Medulloblastoma; Mice; Mice, Nude; Neuroectodermal Tumors, Primitive; Sirolimus; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The rapamycin ester, CCI-779, potently inhibits cell growth in vitro, inhibits tumor growth in vivo, and is currently in Phase I clinical trials. To further understand the relationship between plasma systemic exposure and inhibition of the target Ser/Thr kinase, mTOR/FRAP, two assays have been developed. The first assay involves determination of the 4E suppressor protein (4E-BP1) bound to eukaryotic initiation factor 4E (eIF4E), and the second is direct Western analysis of phosphorylation of residue Thr(70) of 4E-BP1. Under normal growth conditions in vitro, rapamycin caused rapid association of 4E-BP1 with eIF4E within 1 h in Rh30 and GC(3) human tumor cells. Association was persistent up to 16 h. In mice, administration of rapamycin (5 or 20 mg/kg) caused rapid association of 4E-BP1 with eIF4E within 4 h in both human colon adenocarcinoma GC(3) and rhabdomyosarcoma Rh30 xenografts. Using phospho-specific antibody against Thr(70) of 4E-BP1, rapid and persistent dephosphorylation within 30 min of exposure to rapamycin was detected in Rh18 rhabdomyosarcoma cells. Evaluation of CCI-779 against Rh18 xenografts showed this tumor to be growth inhibited at daily dose levels of > or =8.7 mg/kg. Because immunoblotting may be more suitable for assaying tumor biopsy tissue, a "blinded" comparison between the effect of CCI-779 on Thr(70) phosphorylation and growth inhibition of human tumor xenografts was undertaken. Mice were treated daily for 5 days with CCI-779 (20 mg/kg/day) or with drug vehicle, and tumor diameters were measured. Tumors were excised 1 h after the final administration and frozen, and phospho Thr(70) was determined by Western blot analysis. The correlation coefficient for decreases in Thr(70) phosphorylation and growth inhibition was high (r(2), 0.99). The results indicate that an assay of decreases in phosphorylation of Thr(70) of 4E-BP1 may be a useful surrogate for determining the inhibition of mTOR activity in tumor specimens.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Blotting, Western; Carrier Proteins; Cell Cycle Proteins; Cell Division; Eukaryotic Initiation Factor-4E; Eukaryotic Initiation Factors; Humans; Immunoblotting; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Neoplasms; Peptide Initiation Factors; Phosphoproteins; Phosphorylation; Protein Binding; Rhabdomyosarcoma; Sirolimus; Time Factors; Tumor Cells, Cultured

PTEN phosphatase acts as a tumor suppressor by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. It is unclear which downstream components of this pathway are necessary for oncogenic transformation. In this report we show that transformed cells of PTEN(+/-) mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation. Pharmacological inactivation of mTOR/RAFT/FRAP reduced neoplastic proliferation, tumor size, and p70/S6 kinase activity, but did not affect the status of Akt. These data suggest that p70/S6K and possibly other targets of mTOR contribute significantly to tumor development and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.

Topics: Alleles; Animals; Base Sequence; Cell Transformation, Neoplastic; DNA Primers; Female; Humans; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases; Phosphoric Monoester Hydrolases; Protein Kinase Inhibitors; Protein Kinases; PTEN Phosphohydrolase; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Uterine Neoplasms

Recent evidence places the FRAP/mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway, which is up-regulated in multiple cancers because of loss of the PTEN tumor suppressor gene. We performed biological and biochemical studies to determine whether PTEN-deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR by using the rapamycin derivative CCI-779. In vitro and in vivo studies of isogenic PTEN(+/+) and PTEN(-/-) mouse cells as well as human cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP/mTOR inhibition. Enhanced tumor growth caused by constitutive activation of Akt in PTEN(+/+) cells also was reversed by CCI-779 treatment, indicating that FRAP/mTOR functions downstream of Akt in tumorigenesis. Loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, providing evidence for activation of the FRAP/mTOR pathway in these cells. Differential sensitivity to CCI-779 was not explained by differences in biochemical blockade of the FRAP/mTOR pathway, because S6 phosphorylation was inhibited in sensitive and resistant cell lines. These results provide rationale for testing FRAP/mTOR inhibitors in PTEN null human cancers.

Topics: Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins; Cell Cycle Proteins; Cells, Cultured; Eukaryotic Initiation Factors; Humans; Immunophilins; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Knockout; Mice, Nude; Mice, SCID; Neoplasms, Experimental; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Tumor Suppressor Proteins

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Drosophila Proteins; Enzyme Inhibitors; Focal Adhesion Kinase 2; Humans; Mice; Mice, Knockout; Mutation; Neoplasms, Experimental; Phosphoinositide-3 Kinase Inhibitors; Phosphoric Monoester Hydrolases; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; PTEN Phosphohydrolase; Receptor Protein-Tyrosine Kinases; Signal Transduction; Sirolimus; Tumor Suppressor Proteins

The mammalian target of rapamycin (mTOR) is a central regulator of G1 cell cycle protein synthesis that precedes commitment to normal cellular replication. We have studied the effect of cell cycle inhibitor-779 (CCI-779), a rapamycin ester that inhibits mTOR function, on the proliferation of a panel of breast cancer cell lines. Six of eight lines studied were sensitive (IC(50)< or = 50 nM) and two lines were resistant (IC(50)>1.0 microM) to CCI-779. Sensitive lines were estrogen dependent (MCF-7, BT-474, T-47D), or lacked expression of the tumor suppressor PTEN (MDA-MB-468, BT-549), and/or overexpressed the Her-2/neu oncogene (SKBR-3, BT-474). Resistant lines (MDA-MB-435, MDA-MB-231) shared none of these properties. CCI-779 (50 nM) inhibited mTOR function in both a sensitive and a resistant line. In nu/nu mouse xenografts, CCI-779 inhibited growth of MDA-MB-468 (sensitive) but not MDA-MB-435 resistant tumors. Treatment of sensitive lines with CCI-779 resulted in a decrease in D-type cyclin and c-myc levels and an increase in p27(kip-1) levels. There was good correlation between activation of the Akt pathway and sensitivity to CCI-779. Amplification of mTOR-regulated p70S6 kinase, which is downstream of Akt, may also have conferred CCI-779 sensitivity to MCF-7 cells. Taken together, the data suggest that mTOR may be a good target for breast cancer therapy, especially in tumors with Akt activation resulting from either growth factor dependency or loss of PTEN function.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Mice; Mice, Nude; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents; Cell Cycle; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Drug Industry; Genes, Tumor Suppressor; Humans; Immunosuppressive Agents; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins