sirolimus and Kidney-Neoplasms

In the last fifteen years a better understanding of the biological processes promoting tumour growth and progression led to an impressive revolution in metastatic renal cell carcinoma (mRCC) treatment landscape. Angiogenesis plays a critical role in the pathogenesis of RCC. These biological evidences led to targeted therapies interfering with vascular endothelial growth factor and mammalian target of rapamycin pathway. Another big step in the RCC therapeutic landscape was recently made because of the understanding of the interplay between angiogenesis and immune cells. Dual immune checkpoint inhibitors (ICIs) and ICIs plus tyrosine kinase inhibitors (TKI) combinations have been approved considering overall survival benefit compared to targeted therapies as first line treatment. We summarize the activity and the biological rationale of ICIs combinations as mRCC first line therapy. Additionally, we review the clinical and biological criteria useful to guide clinicians in the choice of treatment sequencing focusing on ICIs combinations resistance mechanisms.

Topics: Biological Factors; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Sirolimus; Vascular Endothelial Growth Factor A

Potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex (TSC) have been shown. Currently everolimus (a rapalog) is only approved for TSC-associated renal angiomyolipoma and subependymal giant cell astrocytoma (SEGA), but not other manifestations of TSC. A systematic review needs to establish evidence for rapamycin or rapalogs for various manifestations in TSC. This is an updated review.. To determine the effectiveness of rapamycin or rapalogs in people with TSC for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.. We identified relevant studies from the Cochrane-Central-Register-of-Controlled-Trials (CENTRAL), Ovid MEDLINE and ongoing trials registries with no language restrictions. We searched conference proceedings and abstract books of conferences. Date of the last searches: 15 July 2022.. Randomised controlled trials (RCTs) or quasi-RCTs of rapamycin or rapalogs in people with TSC.. Two review authors independently extracted data and assessed the risk of bias of each study; a third review author verified the extracted data and risk of bias decisions. We assessed the certainty of the evidence using GRADE.. The current update added seven RCTs, bringing the total number to 10 RCTs (with 1008 participants aged 3 months to 65 years; 484 males). All TSC diagnoses were by consensus criteria as a minimum. In parallel studies, 645 participants received active interventions and 340 placebo. Evidence is low-to-high certainty and study quality is mixed; mostly a low risk of bias across domains, but one study had a high risk of performance bias (lack of blinding) and three studies had a high risk of attrition bias. Manufacturers of the investigational products supported eight studies. Systemic administration Six studies (703 participants) administered everolimus (rapalog) orally. More participants in the intervention arm reduced renal angiomyolipoma size by 50% (risk ratio (RR) 24.69, 95% confidence interval (CI) 3.51 to 173.41; P = 0.001; 2 studies, 162 participants, high-certainty evidence). In the intervention arm, more participants in the intervention arm reduced SEGA tumour size by 50% (RR 27.85, 95% CI 1.74 to 444.82; P = 0.02; 1 study; 117 participants; moderate-certainty evidence) ,and reported more skin responses (RR 5.78, 95% CI 2.30 to 14.52; P = 0.0002; 2 studies; 224 participants; high-certainty evidence). In one 18-week study (366 participants), the intervention led to 25% fewer seizures (RR 1.63, 95% CI 1.27 to 2.09; P = 0.0001) or 50% fewer seizures (RR 2.28, 95% CI 1.44 to 3.60; P = 0.0004); but there was no difference in numbers being seizure-free (RR 5.30, 95% CI 0.69 to 40.57; P = 0.11) (moderate-certainty evidence). One study (42 participants) showed no difference in neurocognitive, neuropsychiatry, behavioural, sensory and motor development (low-certainty evidence). Total adverse events (AEs) did not differ between groups (RR 1.09, 95% CI 0.97 to 1.22; P = 0.16; 5 studies; 680 participants; high-certainty evidence). However, the intervention group experienced more AEs resulting in withdrawal, interruption of treatment, or reduced dose (RR 2.61, 95% CI 1.58 to 4.33; P = 0.0002; 4 studies; 633 participants; high-certainty evidence and also reported more severe AEs (RR 2.35, 95% CI 0.99 to 5.58; P = 0.05; 2 studies; 413 participants; high-certainty evidence). Topical (skin) administration Four studies (305 participants) administered rapamycin topically. More participants in the intervention arm showed a response to skin lesions (RR 2.72, 95% CI 1.76 to 4.18; P < 0.00001; 2 studies; 187 participants; high-certainty evidence) and more participants in t. Oral everolimus reduces the size of SEGA and renal angiomyolipoma by 50%, reduces seizure frequency by 25% and 50% and implements beneficial effects on skin lesions with no difference in the total number of AEs compared to placebo; however, more participants in the treatment group required a dose reduction, interruption or withdrawal and marginally more experienced serious AEs compared to placebo. Topical rapamycin increases the response to skin lesions and facial angiofibroma, an improvement score, satisfaction and the risk of any AE, but not severe adverse events. With caution regarding the risk of severe AEs, this review supports oral everolimus for renal angiomyolipoma, SEGA, seizure, and skin lesions, and topical rapamycin for facial angiofibroma.

Topics: Adult; Angiofibroma; Angiomyolipoma; Astrocytoma; Everolimus; Humans; Kidney Neoplasms; Male; MTOR Inhibitors; Sirolimus; Tuberous Sclerosis

Renal cell carcinoma (RCC) is one of the most lethal urological cancers, highly resistant to chemo and radiotherapy. Obesity and smoking are the best-known risk factors of RCC, both related to oxidative stress presence, suggesting a significant role in RCC development and maintenance. Surgical resection is the treatment of choice for localized RCC; however, this neoplasia is hardly diagnosable at its initial stages, occurring commonly in late phases and even when metastasis is already present. Systemic therapies are the option against RCC in these more advanced stages, such as cytokine therapy or a combination of tyrosine kinase inhibitors with immunotherapies; nevertheless, these strategies are still insufficient. A field poorly analyzed in this neoplasia is the status of cell signaling pathways sensible to the redox state, which have been associated with the development and maintenance of RCC. This review focuses on alterations reported in the following redox-sensitive molecules and signaling pathways in RCC: mitogen-activated protein kinases, protein kinase B (AKT)/tuberous sclerosis complex 2/mammalian target of rapamycin C1, AKT/glycogen synthase kinase 3/β-catenin, nuclear factor κB/inhibitor of κB/epidermal growth factor receptor, and protein kinase Cζ/cut-like homeodomain protein/factor inhibiting hypoxia-inducible factor (HIF)/HIF as potential targets for redox therapy.

Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Oxidation-Reduction; Signal Transduction; Sirolimus

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

Renal cell carcinoma (RCC) is a commonly diagnosed and histologically diverse urologic malignancy. Clear cell RCC (ccRCC) is by far the most common, followed by the papillary and chromophobe subtypes. Sarcomatoid differentiation is a morphologic change that can be seen in all subtypes that typically portends a poor prognosis. In the past, treatment options for RCC were limited to cytokine-based therapy with a high-toxicity profile and low response rate. An increased understanding of the molecular basis of RCC has led to substantial improvement in treatment options in the form of targeted therapy and immunotherapy. A significant early discovery in RCC was frequent inactivation of the Von Hippel Lindau gene in ccRCC, which ultimately led to the development of vascular endothelial growth factor and mammalian target of rapamycin inhibitors. Further genomic sequencing of ccRCC tumors has identified other common mutations including BAP-1, PBRM1, SETD2, and PIK3CA. Many recent studies have explored how these mutations can affect prognosis and response to treatment. Likewise, papillary RCC has also been studied at the molecular level, which has shown a high level of mutations in the MET gene; early clinical data suggest the utility of MET targeted therapy. Finally, regarding the rarer sarcomatoid tumors, mutations in TP53 and NF2 may be important to their development. As we continue to learn more about what drives RCC at the molecular level, treatment options for RCC patients are diversifying.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Disease-Free Survival; DNA Mutational Analysis; Genomics; Humans; Immunotherapy; Kidney; Kidney Neoplasms; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Nephrectomy; Prognosis; Risk Assessment; Sirolimus

Perivascular epithelioid cell tumor (PEComa) is a family of mesenchymal tumors. Conventional chemotherapy has little activity in this disease, but case reports are available on the activity of mammalian target of rapamycin inhibitors (e.g. sirolimus and temsirolimus). Pharmacokinetic assays of sirolimus are available as this drug has a precise therapeutic window and blood levels might be influenced by CYP3A4 polymorphisms and drug interactions. We report on a case of a patient with metastatic, progressive PEComa who started sirolimus at a dose of 5 mg/day with evidence of grade (G) 3 mucositis, G2 thrombocytopenia, and G1 leucopenia 10 days after the treatment started, in absence of concomitant medications or prohibited food assumption. Elevated sirolimus blood levels were detected (156.8 ng/ml). Sirolimus was stopped, and toxicity resolved in 5 weeks. Computed tomography scan 2 months after the treatment started showed a partial response (RECIST). After toxicity resolution, the patient restarted sirolimus at a dose of 1 mg/day, with blood levels in the range of 10-20 ng/ml. Tumor response was confirmed and maintained, and the patient is still under treatment 18 months later, with no additional adverse effects. Genetic analysis of five selected polymorphisms (rs2740574, rs776746, rs1128503, rs2032582, and rs1045642) in drug metabolism enzymes and transporters did not provide a clear explanation of the observed unusual pharmacokinetic. This case confirms the activity of mammalian target of rapamycin inhibitors in PEComa and strengthens the importance of pharmacokinetic drug blood levels monitoring in patients treated with sirolimus. In our patient, after dose adjustment, sirolimus could be restarted with a prolonged clinical benefit and no additional toxicity.

Topics: Antibiotics, Antineoplastic; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Perivascular Epithelioid Cell Neoplasms; Sirolimus

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

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

In adult tuberous sclerosis complex (TSC) patients, renal complications are the leading cause of death. Beginning in childhood, up to 80 % of patients develop renal angiomyolipoma characterized by a size-dependent risk of life-threatening bleeding. After discovery of the two causative genes, TSC1 and TSC2, and the role of mammalian target of rapamycin (mTOR) regulation in the pathogenesis of TSC, an increasing number of clinical studies evaluating mTOR inhibition in TSC patients have shown impressive results in many organ manifestations, such as brain, lung, and kidney. For renal angiomyolipoma, mTOR inhibitor treatment fundamentally changed the approach from preventive embolization or even partial nephrectomy to everolimus treatment in order to preserve kidney function.

Topics: Angiomyolipoma; Antineoplastic Agents; Child; Embolization, Therapeutic; Everolimus; Humans; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Mutation; Nephrectomy; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

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

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; 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Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; 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Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; 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Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

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

Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt-Hogg-Dubé syndrome-associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron-sparing. The timing of surgery is the most critical element for postoperative renal function, which is one of the important prognostic factors for Birt-Hogg-Dubé syndrome patients. The folliculin gene (FLCN) that is responsible for Birt-Hogg-Dubé syndrome was isolated as a novel tumor suppressor for kidney cancer. Recent studies using murine models for FLCN, a protein encoded by the FLCN gene, and its two binding partners, folliculin-interacting protein 1 (FNIP1) and folliculin-interacting protein 2 (FNIP2), have uncovered important roles for FLCN, FNIP1 and FNIP2 in cell metabolism, which include AMP-activated protein kinase-mediated energy sensing, Ppargc1a-driven mitochondrial oxidative phosphorylation and mTORC1-dependent cell proliferation. Birt-Hogg-Dubé syndrome is a hereditary hamartoma syndrome, which is triggered by metabolic alterations under a functional loss of FLCN/FNIP1/FNIP2 complex, a critical regulator of kidney cell proliferation rate; a mechanistic insight into the FLCN/FNIP1/FNIP2 pathway could provide us a basis for developing new therapeutics for kidney cancer.

Topics: Animals; Birt-Hogg-Dube Syndrome; Carrier Proteins; Gene Knockout Techniques; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Mutation; Neoplasms, Experimental; Nephrectomy; Proto-Oncogene Proteins; Rats; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

Second- and third-line treatments are more and more frequently administered to metastatic renal cell carcinoma (mRCC) patients.. Here we discuss the various levels of evidence supporting presently available recommendations, trying to address a number of as yet unanswered issues, and also to take a glowing glance at the future. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for relevant studies.. Until recently, with regard to choosing the second line treatment after the failure of therapy with vascular endothelial growth factor receptors-tyrosine kinase inhibitors (VEGFR-TKIs), the continued inhibition of the VEGF/VEGR pathway, or else the switch to an mTOR inhibitor, is recommended. These two options are characterized by partly different targets, completely different toxicity profiles, but a comparable efficacy. This scenario will change soon, after the publication of two randomized, controlled, phase III trials in which cabozantinib and nivolumab proved to be superior as compared to everolimus. As regards third line treatment, where a sequence of two VEGFR-TKIs has been used beforehand, the choice is represented by the mTOR inhibitor everolimus, whilst if a VEGFR-TKI followed by everolimus has been chosen, a return to VEGF pathway inhibition is suggested.

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Nivolumab; Protein Kinase Inhibitors; Pyridines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; TOR Serine-Threonine Kinases

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

Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency) for tuberous sclerosis complex-associated renal angiomyolipoma and subependymal giant cell astrocytoma, applications for other manifestations of tuberous sclerosis complex have not yet been established. A systematic review is necessary to establish the clinical value of rapamycin or rapalogs for various manifestations in tuberous sclerosis complex.. To determine the effectiveness of rapamycin or rapalogs in people with tuberous sclerosis complex for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.. Relevant studies were identified by authors from the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, and clinicaltrials.gov. Relevant resources were also searched by the authors, such as conference proceedings and abstract books of conferences, from e.g. the Tuberous Sclerosis Complex International Research Conferences, other tuberous sclerosis complex-related conferences and the Human Genome Meeting. We did not restrict the searches by language as long as English translations were available for non-English reports.Date of the last searches: 14 March 2016.. Randomized or quasi-randomized studies of rapamycin or rapalogs in people with tuberous sclerosis complex.. Data were independently extracted by two authors using standard acquisition forms. The data collection was verified by one author. The risk of bias of each study was independently assessed by two authors and verified by one author.. Three placebo-controlled studies with a total of 263 participants (age range 0.8 to 61 years old, 122 males and 141 females, with variable lengths of study duration) were included in the review. We found high-quality evidence except for response to skin lesions which was judged to be low quality due to the risk of attrition bias. Overall, there are 175 participants in the treatment arm (rapamycin or everolimus) and 88 in the placebo arm. Participants all had tuberous sclerosis complex as proven by consensus diagnostic criteria as a minimum. The quality in the description of the study methods was mixed, although we assessed most domains as having a low risk of bias. Blinding of treatment arms was successfully carried out in all of the studies. However, two studies did not report allocation concealment. Two of the included studies were funded by Novartis Pharmaceuticals.Two studies (235 participants) used oral (systemic) administration of everolimus (rapalog). These studies reported response to tumour size in terms of the number of individuals with a reduction in the total volume of tumours to 50% or more relative to baseline. Significantly more participants in the treatment arm (two studies, 162 participants, high quality evidence) achieved a 50% reduction in renal angiomyolipoma size, risk ratio 24.69 (95% confidence interval 3.51 to 173.41) (P = 0.001). For the sub-ependymal giant cell astrocytoma, our analysis of one study (117 participants, high quality evidence) showed significantly more participants in the treatment arm achieved a 50% reduction in tumour size, risk ratio 27.85 (95% confidence interval 1.74 to 444.82) (P = 0.02). The proportion of participants who showed a skin response from the two included studies analysed was significantly increased in the treatment arms, risk ratio 5.78 (95% confidence interval 2.30 to 14.52) (P = 0.0002) (two studies, 224 participants, high quality evidence). In one study (117 participants), the median change of seizure frequency was -2.9 in 24 hours (95% confidence interval -4.0 to -1.0) in the treatment group versus -4.1 in 24 hour (95% confidence interval -10.9 to 5.8) in the placebo group. In one study, one out of 79 participants in the treatment group versus three of 39 in placebo group had increased blood creatinine levels, while the median percentage change of forced expiratory volume at one second in the treatment arm was -1% compared to -4% in the placebo arm. In one study (117 participants, high quality. We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.

Topics: Administration, Oral; Administration, Topical; Angiolipoma; Astrocytoma; Brain Neoplasms; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Randomized Controlled Trials as Topic; Seizures; Sirolimus; Skin Diseases; Tuberous Sclerosis; Tumor Burden

Lymphangioleiomyomatosis is a rare multisystem disease predominantly affecting women that can occur sporadically or in association with tuberous sclerosis. Lung cysts progressively replace the lung parenchyma, which leads to dyspnea, recurrent pneumothorax, and in some cases respiratory failure. Patients may also have lymphatic disease in the thorax, abdomen, and pelvis, and renal angiomyolipomas. Treatment includes supportive care, bronchodilators, and for those with progressive disease, mammalian target of rapamycin (mTOR) inhibitors.

Topics: Angiomyolipoma; Antibiotics, Antineoplastic; Bronchodilator Agents; Everolimus; Humans; Kidney Neoplasms; Lung Neoplasms; Lymphangioleiomyomatosis; Pleurodesis; Pneumothorax; Sirolimus; Tomography, X-Ray Computed; Tuberous Sclerosis; Ultrasonography

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

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

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

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

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Indoles; Kidney Neoplasms; Male; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrroles; Sirolimus

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 inhibitor (mTORI) everolimus and the tyrosine kinase inhibitor (TKI) axitinib are the only two post-first-line treatment options for metastatic renal cell carcinoma (mRCC) licensed at present. Extrapolation of robust phase III studies suggests that median progression-free survival (PFS) is similar between agents. This presents a dilemma for the physician planning treatment for their patients with mRCC: should they be treated with a TKI-mTORI or a TKI-TKI sequence? The lack of direct comparison between axitinib and everolimus leaves the clinician without clear guidance on the optimal choice in second-line therapy. In phase III studies, both post first-line everolimus and axitinib have been shown to delay disease progression; however, cumulative toxicity with sequential use of TKIs may result in more treatment interruptions or dose reductions or increased likelihood of adverse events. While everolimus exerts a tolerability advantage, axitinib is associated with higher response rate and a similar PFS benefit. Proven superiority cannot be used to guide treatment sequence selection in mRCC. Instead, therapeutic planning requires us to take a long-term view of our patient's treatment that includes quality of life and a balance between symptom control, adverse event management and avoidance of unnecessary drug interruptions or dose reductions. In the absence of curative therapies, sustaining a patient's quality of life is a major goal throughout the course of treatment and choosing a second-line agent that is able to adequately achieve this by limiting adverse events should be a priority.

Topics: Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Disease Progression; Everolimus; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Protein Kinase Inhibitors; Quality of Life; Sirolimus; Vascular Endothelial Growth Factor A

We evaluate the efficacy and safety of sirolimus in the treatment of renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.. A systematic search of MEDLINE®, Embase®, ACP (American College of Physicians) Journal Club, Cochrane CENTRAL (Central Register of Controlled Trials) and Cochrane Database of Systematic Reviews was performed. A secondary hand search was performed in relevant journals, references and the grey literature. The screening, quality assessment and data extraction of the retrieved articles were independently performed by 2 reviewers in duplicate. Studies that reported an angiomyolipoma response or adverse events after the treatment of sirolimus were included in the analysis.. Four prospective nonrandomized studies involving 94 patients were included in the study. The overall response rate of angiomyolipoma was 46.8% (44 of 94) in the first year. In the second year the angiomyolipoma response rate for those patients still being treated with sirolimus was 43.5% (20 of 46) and the response rate of the patients whose sirolimus treatment was discontinued was 5% (2 of 40). The most common sirolimus related adverse reactions were stomatitis, respiratory infection, skin lesions and hyperlipidemia, while serious adverse reactions were rarely observed.. This study shows that renal angiomyolipoma shrank during sirolimus therapy but tended to regrow after the therapy was stopped. In general, sirolimus is an effective and safe therapy for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.

Topics: Angiomyolipoma; Antibiotics, Antineoplastic; Humans; Kidney Neoplasms; Lymphangioleiomyomatosis; Sirolimus; Treatment Outcome; Tuberous Sclerosis

Targeted agents have substantially improved outcomes in metastatic clear cell renal cell carcinoma. However, due to multiple mechanisms of evasive resistance, almost all patients progress at some point and may require subsequent therapies. Various agents have been explored after failure of first-line treatment in randomized clinical trials. However, so far few questions about the optimal sequence have been answered. Both everolimus and axitinib have been considered standard of care after failure of first-line VEGF-TKI; sorafenib has been proposed as an additional option. In clinical practice, several factors may influence the choice of subsequent treatment: these include considerations on appropriate drug exposure in first-line, gained insights on prognostic and predictive factors as well as mechanisms of resistance. Once the decision in second-line has been made and treatment has been initiated, treating physicians may already be challenged by the question of what to offer in third- and later lines. Treatment beyond second-line treatment isn't supported by strong evidence, and at this stage of disease, retrospective reports on rechallenge may help to guide decisions. In addition, local treatment approaches including metastasectomy and stereotactic radiosurgery may help to optimize outcomes in all treatment lines.

Topics: Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Patient Selection; Sirolimus; Treatment Outcome

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

Treatment of metastatic renal cell carcinoma has radically changed during the last decade with the approval of new drugs, antiangiogenic agents and mammalian targets of rapamycin (m-TOR) inhibitors. The outcome of metastatic clear-cell carcinoma has been significantly improved, while other entities such as metastatic papillary renal cell carcinoma are still associated with a poor prognosis. To date, there is no standard guideline for metastatic non clear cell carcinoma. We report the case of a 68-year-old patient with a pulmonary metastatic evolution of a papillary kidney cancer who has had more than 3 years disease progression-free survival and is under ongoing treatment with m-TOR inhibitors.

Topics: Aged; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Protein Kinase Inhibitors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; 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

The incidence of renal cell cancer (RCC) has been steadily increasing over the past decade. Advances in understanding the pathophysiology and carcinogenesis RCC have led to the development of novel therapies that target molecular pathways. Everolimus is a synthetic, orally available analogue of rapamycin that inhibits the activation of mTOR. Everolimus extended progression-free survival in RCC patients from 1.9 months (for patients receiving a placebo) to 4.9 months. Grades 3 and 4 adverse events include stomatitis, fatigue, pneumonitis, infections, asthenia, diarrhea, mucosal inflammation, dyspnea, rash, anorexia and dry skin. Grades 3 and 4 laboratory abnormalities include lymphopenia, anemia, thrombocytopenia, hyperglycemia, hypophosphatemia, hypercholesterolemia, hypertriglycemia, elevated creatinine, elevated alkaline phosphatase, elevated aspartate aminotransferase and elevated alanine aminotransferase. Studies have been conducted to evaluate any synergistic effect of combination therapies and continue to need to be further evaluated.. A systematic review of medical literature for everolimus as a single agent or combination was completed using PubMed.. Everolimus has significant clinical benefit and is well tolerated with reversible side effects as second- or third-line therapy for treating RCC. The next phase of research for everolimus is determining patient selection based on mTOR profile utilizing skills such as proteomics and genomics.

Topics: Administration, Oral; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Drug Design; Everolimus; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Patient Selection; Sirolimus; TOR Serine-Threonine Kinases

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

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

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

Patients with metastatic renal cell carcinoma (mRCC) and a good performance status typically receive an anti-vascular endothelial growth factor receptor (VEGFR) TKI (sunitinib or pazopanib) as initial therapy. Upon disease progression or intolerance, there are four orally administered agents approved in the second-line setting (including cytokine-refractory). However, head-to-head comparative trial data are limited. In this study, an indirect statistical comparison of safety and efficacy was undertaken between axitinib, sorafenib, pazopanib and everolimus in second-line therapy mRCC.. A systematic review of major databases was conducted from January 2005 to June 2013 for randomized controlled trials (RCTs) evaluating at least one of the four agents in second-line mRCC. Bayesian mixed treatment comparison models were fitted to assess relative effectiveness on multiple endpoints such as objective response rates, dose-limiting grade III/IV toxicities, treatment discontinuations and progression-free survival (PFS).. Four RCTs met the inclusion criteria. All four agents seem able to induce tumor shrinkage and to provide patients with a clinically meaningful PFS benefit. Axitinib was superior to pazopanib [hazard ratio (HR) 0.64; 95 % credible interval (95 % Crl) 0.42-0.96] and sorafenib (HR 0.70; 95 % Crl 0.57-0.87) in terms of PFS. However, axitinib was associated with an elevated risk of fatigue and to a lesser extent stomatitis.. Keeping in mind the caveats associated with cross-trial statistical comparisons, axitinib provides superior PFS relative to pazopanib and sorafenib. Everolimus, an mammalian target of rapamycin inhibitor, is mechanistically distinct from the other agents and remains a useful option for patient's post-anti-VEGFR TKI failure.

Topics: Antineoplastic Agents; Axitinib; Bayes Theorem; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides

To describe the role of mammalian target of rapamycin (mTOR) inhibition in the treatment of tuberous sclerosis complex (TSC) patients with renal angiomyolipoma in relation to available clinical data and clinical practice guidance for the nurse practitioner (NP).. A review of the scientific literature, key clinical congresses, and key clinical trials.. TSC-associated renal angiomyolipomas have a propensity to grow over time and predispose patients to serious and life-threatening consequences. Surgery or invasive interventional therapies may not be the most optimal treatments because of the multiple, bilateral growth pattern of TSC-associated renal angiomyolipomas. Targeted therapies, such as mTOR inhibitors, which have demonstrated efficacy in maintaining and reducing renal angiomyolipoma size, are of great benefit to patients.. Treatment with everolimus, an oral mTOR inhibitor, offers patients a noninvasive pharmacotherapeutic treatment option. The NP, as a key member of the healthcare team overseeing TSC patients, must be knowledgeable about the safety and efficacy of mTOR inhibitors as their use in the patient population increases.

Topics: Angiomyolipoma; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

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

We experienced a case of interstitial lung disease (ILD) that occurred one year after the start of everolimus therapy for renal cell carcinoma. The pathological features included interstitial pneumonia with granuloma formation. Everolimus is known to cause ILD; however, its pathology is unclear. Granuloma-forming interstitial pneumonia associated with everolimus is uncommon, although it may be one of the pathological patterns associated with everolimus-induced ILD. This is a slow-onset case of everolimus-induced ILD in a patient with renal cell carcinoma. Physicians should thus be aware of the potential for the development of ILD at any time during the administration of everolimus therapy.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Granuloma, Respiratory Tract; Humans; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus; Time Factors

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

The introduction of novel anti-angiogenic therapies has greatly improved the outcome of patients with metastatic renal cell carcinoma (mRCC). The use of these therapies in combination or sequentially is proposed to provide greater efficacy. We have reviewed completed and ongoing clinical trials in mRCC that have reported efficacy and/or safety data of novel therapies used in combination or sequentially. Bevacizumab appears to be a useful partner when combined with interferon (IFN), while controversial results have been reported when combined with temsirolimus and everolimus. Other combinations appear to have unacceptable tolerability or require dose or schedule optimization. Sequencing data provide a clear indication that multiple lines of treatment may extend survival. The 'ideal' sequence, however, is still unknown. In conclusion, novel therapies used in combination or sequentially have potential to provide optimised treatment and patient outcomes in mRCC. The results from ongoing/planned trials are expected to help shape future therapy.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Administration Schedule; Humans; Immunotherapy; Interferons; Interleukin-2; Kidney Neoplasms; Molecular Targeted Therapy; Neovascularization, Pathologic; Protein Kinase Inhibitors; 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

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder promoting the development of benign tumors in multiple organ systems, including the skin, brain, and kidneys. In contrast to asymptomatic spontaneous angiomyolipomas, angiomyolipomas in patients with TSC are mostly bilateral and are accompanied by other typical clinical features of TSC. Kidney angiomyolipomas are benign tumors composed of blood vessels, adipose tissue, and smooth muscle and are associated with spontaneous bleeding and potential life-threatening hemorrhage if >4 cm. Current treatment options for angiomyolipoma are focused on conserving kidney function and limiting potentially fatal hemorrhage. TSC is caused by mutations in either TSC1 or TSC2 suppressor genes, resulting in increased mammalian target of rapamycin (mTOR) activity. Preclinical studies have shown the efficacy of mTOR inhibitors in inhibiting the growth of patient-derived cell lines and suppressing tumors in animal models of TSC. In the clinical setting, mTOR inhibitors have shown promising efficacy in patients with TSC-associated angiomyolipomas and subependymal giant cell astrocytomas. This review explores the diagnosis and current management of TSC-associated angiomyolipomas, the relevance of the mTOR pathway in the pathogenesis of TSC, and the potential promise of mTOR-inhibitor therapy as a systemic therapeutic approach to treat the underlying cause of TSC.

Topics: Angiomyolipoma; Everolimus; Humans; Kidney Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tuberous Sclerosis

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

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

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

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

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

Patients with tuberous sclerosis complex are at great risk of developing renal lesions as part of their disease. These lesions include renal cysts and tumors. Significant advances in understanding the cell biology of these renal lesions has already led to clinical trials demonstrating that pharmacological interventions are likely possible. This review focuses on the pathology of these renal lesions, their underlying cell biology, and the possible therapeutic strategies that may prove to significantly improve care for these patients.

Topics: Angiomyolipoma; Antibiotics, Antineoplastic; Child; Humans; Kidney Diseases, Cystic; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Proteins; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

To review clinical trials and main characteristics of everolimus, with focus on treatment of advanced renal cell carcinoma.. Pertinent data were identified primarily through a search of MEDLINE and PubMed (1966-November 2010) using the primary search terms everolimus, RAD001, renal cell carcinoma, and mTOR inhibitors.. Studies evaluating the safety and efficacy of everolimus in patients with cancer were evaluated, including Phase 1, 2, and 3 trials. Preference was given to Phase 2 and 3 studies evaluating use of everolimus in patients with renal cell carcinoma.. Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor approved for the management of patients with advanced renal cell carcinoma who progressed on tyrosine kinase inhibitor therapy. Actions of everolimus within the mTOR pathway result in decreased protein synthesis and cell cycle arrest, as well as decreased angiogenesis. A usual starting dose for patients with renal cell carcinoma is 10 mg daily. Everolimus undergoes extensive hepatic metabolism, primarily through the CYP3A4 isoenzyme, which predisposes it to drug interactions with inducers and inhibitors of this enzyme. Most commonly reported adverse events associated with everolimus include anemia, hyperglycemia, hypercholesterolemia, mucositis, fatigue, and rash. Approval of everolimus was based on the results of a Phase 3 trial that demonstrated an increase in median progression-free survival by 2.1 months in patients receiving everolimus therapy as compared to placebo. The drug was recently added to the National Comprehensive Cancer Network guidelines as a treatment option for patients with advanced renal cell carcinoma who have progressed on tyrosine kinase therapy.. Based on a review of the currently available literature, everolimus provides a safe and efficacious treatment option for patients with renal cell carcinoma who have progressed on treatment with sunitinib and/or sorafenib.

Topics: Carcinoma, Renal Cell; Drug Costs; Drug Interactions; Drug Resistance, Neoplasm; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Tuberous sclerosis complex (TSC) is an inherited disorder characterized by hamartomas in different body organs, mainly in the brain, skin, kidney, liver, lung, and heart. The clinical manifestations of TSC are the result of a mutation of one of two tumor suppressor genes, TSC1 and TSC2. Cutaneous findings in TSC should be regarded as cutaneous signs of a pivotal systemic disease. The authors elucidate the variety of neoplasms seen in TSC patients, along with their clinical significance, and suggest suitable evaluation and management strategies.

Topics: Angiomyolipoma; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Renal Cell; Cell Transformation, Neoplastic; Female; Heart Neoplasms; Humans; Kidney Neoplasms; Lung Neoplasms; Lymphangioleiomyomatosis; Male; Mutation; Radiography; Rhabdomyoma; Sirolimus; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

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

The efficacy of sequential everolimus (RAD001, Afinitor®), an orally administered inhibitor of mammalian target of rapamycin (mTOR), is one of the therapeutic options in patients with advanced renal cell cancer (RCC). The purpose of this review is to discuss the mTOR pathway and to update current knowledge of the role of everolimus in metastatic RCC.. The function of mTOR and its inhibition, the early development trials of everolimus, the Phase II trial that lead to the Phase III study and ultimately to FDA approval are all discussed in this review. Literature utilized for this review consists of PUBMED for both description of the mTOR pathway and its role, in addition to publications using everolimus in RCC.. Everolimus is currently the only agent with a proven progression-free survival improvement for patients who progressed on a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Future studies may further shed light on the most optimal use of everolimus.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease Progression; Everolimus; Female; Humans; Kidney Neoplasms; Male; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

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

mTOR-inhibitors are part of targeted agents and are already in use in the clinic, especially for treatment of metastatic renal cell carcinoma. Distinct from conventional chemotherapeutics, targeted agents imply chronic treatment, which has changed our perspective on the commerce of adverse events (AE). In principle, mTOR-inhibitors are associated with a broad number of AEs. The occurrence of stomatitis, infection, pneumonitis, hyperlipidemia and hyperglycemia are considered major class effects of mTOR-inhibitors. However, severe adverse events remain scarce among mTOR-inhibitors and support chronic use of these agents. Based on their good clinical tolerability mTOR-inhibitors are prone to be developed in combinational therapies. However, the hepatic metabolism of these agents may limit their use to partners with a distinct metabolism in order to avoid drug interaction. Meanwhile about 40 different trials use mTOR-inhibitors in different tumor entities. The use of mTOR-inhibitors in neuroendocine tumors of the intestine, mantle cell lymphoma and sarcomas has hereby shown to be very promising. The mainstay of therapy already incorporates the use of everolimus in second line and temsirolimus in first line treatment in patients with metastatic renal cell carcinoma.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Interactions; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Neoplasms; Neoplasm Metastasis; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

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

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

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

The treatment objective in the metastatic situation is to delay progression while maintaining the best possible quality of life. Since several targeted therapies with different modes of action already exist, sequence therapy is increasingly being considered. Current data regarding sequential treatment is still insufficient and several approaches are being tested in ongoing clinical studies. Based on current data, guidelines, and the therapeutic algorithms supported by national and international professional associations, the German Cancer Society's interdisciplinary task force on renal cell carcinoma (RCC) recommends the following approach: since the efficacy of cytokines is very limited after a previous cytokine-based therapy has failed, Sorafenib or Sunitinib are the treatment of choice. Treatment with other targeted substances is recommended after first-line therapy has failed as a number of retrospective studies have documented relevant activity. Everolimus currently is the treatment of first choice when VEGF-directed therapy has failed. Based on the results of phase II studies, other tyrosine kinase inhibitors can alternatively be applied.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cytokines; Disease Progression; Drug Administration Schedule; Drug Delivery Systems; Drugs, Investigational; Everolimus; Evidence-Based Medicine; Humans; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Practice Guidelines as Topic; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Survival Rate

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

Everolimus, an orally administered rapamycin analog, has recently been approved by the U.S. Food and Drug Administration for treatment of renal cell carcinoma (RCC) refractory to inhibitors of vascular endothelial growth factor (VEGF) receptor signaling. Everolimus significantly increased progression-free survival (median PFS for the everolimus treated group was 4.0 months versus 1.9 months for the placebo group), although tumor regressions were observed only infrequently. Although the target for everolimus, [the serine-threonine kinase mammalian target of rapamycin (mTOR)] is well established, the mechanism by which this agent retards tumor growth is not well defined. Further, biomarkers that predict tumor sensitivity are still elusive. The mechanism of action, preclinical antitumor activity, and clinical activity of everolimus against RCC are reviewed.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Kidney Neoplasms; Sirolimus

Recent advances in understanding the molecular biology of advanced and metastatic renal cell carcinoma (RCC) have led to the development of several targeted agents that show impressive antitumor efficacy. The integration of these drugs into clinical practice has revolutionized the therapeutic management of RCC.. We reviewed data on all approved targeted agents in the first-line and second-line setting, as well as, studies involving sequential therapy. Data from phase III trials are discussed, and an optional therapeutic algorithm is presented.. Sunitinib should be used as the first-line treatment of choice for good- and intermediate-risk patients according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, whereas temsirolimus is recommended for the poor-risk group. The combination of bevacizumab and INF-alpha can be regarded as an alternative to sunitinib. After cytokine failure, patients should be recommended to sorafenib. Everolimus must be considered after first-line failure of a tyrosine kinase inhibitor (TKI); furthermore, recent evidence suggests sequential use of TKIs before administration of everolimus.. A range of potent drugs are available to patients with metastatic RCC. Treatment decisions should be made carefully taking into consideration that all targeted agents only have a palliative effect with prolongation of life, but do not cure metastatic RCC.

Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Biopsy, Needle; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Delivery Systems; Everolimus; Female; Follow-Up Studies; Humans; Immunohistochemistry; Indoles; Interferon-alpha; Kidney Neoplasms; Male; Maximum Tolerated Dose; Neoplasm Metastasis; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Risk Assessment; Sirolimus; Sorafenib; Sunitinib; Survival Analysis

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment for patients with metastatic RCC (mRCC). Multikinase inhibitors (sunitinib and sorafenib) and the inhibitors of mammalian target of rapamycin (temsirolimus and everolimus) have recently shown superiority over IFN-alpha or placebo; and bevacizumab + IFN-alpha have demonstrated improved activity when compared to IFN-alpha alone in patients with mRCC. Newer anti-vascular endothelial growth factor (VEGF) agents such as axitinib, pazopanib and cediranib are currently under investigation to expand and elucidate future treatment options. Several studies have investigated the synergistic potential of TKIs with a view to blocking multiple signalling pathways simultaneously, but this approach has resulted in a significant increase in toxicity. Sequential TKI administration has demonstrated encouraging results but the optimal sequence of TKIs is yet to be determined. Studies combining TKIs with immunotherapy have resulted in varying degrees of success; with bevacizumab + IFN-alpha being the only studies with positive outcomes. The purpose of this review is to summarize the current evidence supporting the role of TKIs and to discuss potential future directions in the management of mRCC. The role of TKIs as monotherapy, in combination with immunotherapy or other TKIs (combined or sequential approach) will be discussed.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma, Renal Cell; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Historically, there have been few treatment options for patients with advanced renal cell carcinoma (RCC) besides immunotherapy with interleukin-2 and interferon (IFN)-alpha. Targeted therapies have improved clinical outcomes over the past several years. These include the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors sunitinib and sorafenib, which inhibit angiogenic signaling in endothelial cells and vascular pericytes predominantly through VEGFR and platelet-derived growth factor receptor beta. Also included is the anti-VEGF monoclonal antibody bevacizumab used in combination with IFN-alpha. These agents mediate their antitumor effects by interfering with the VEGF signaling pathway, thereby inhibiting angiogenesis and causing tumor shrinkage. However, ultimately, most patients develop resistance and experience disease progression during VEGF/VEGFR-targeted therapy, and until the recent approval of the mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001), there were no agents available with proven activity in this setting. This review describes the clinical development of everolimus in advanced RCC and the rationale for the use of mTOR inhibitors after failure of VEGF/VEGFR inhibitors.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Sirolimus

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

Topics: Adenocarcinoma; Angiomyolipoma; Antibiotics, Antineoplastic; Astrocytoma; Brain Neoplasms; Breast Neoplasms; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Kidney Neoplasms; Lung Neoplasms; Mutation; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

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

Renal cell carcinoma accounts for 3% of all malignant tumours. Until a few years ago, immunotherapy (interferon and/or interleukin-2) was the only approved option in the metastatic setting. Better knowledge of renal cell cancer biology drew attention on the fundamental role of angiogenesis. Several strategies targeting angiogenesis have been developed including VEGF ("Vascular Endothelial Growth Factor") and VEGFR inhibitors. They are now the usual treatment in first line. Until recently, no standard treatment was available after failure under or after these inhibitors. Everolimus (Afinitor), a mTOR ("mammalian Target Of Rapamycin") inhibitor, has just been validated and reimbursed in this setting. In this paper, we will review the mechanism of action and the clinical results of everolimus.

Topics: Carcinoma, Renal Cell; Everolimus; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Protein Serine-Threonine Kinases; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

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

Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. Everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for "REnal Cell cancer treatment with Oral RAD001 given Daily"), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. Everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus, one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome, will provide insight into its future place in NET therapy. The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Therapy, Combination; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Neuroendocrine Tumors; Octreotide; Practice Guidelines as Topic; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Both experimental and clinical researches focusing on advanced kidney cancer have increased continuously since the successful introduction of targeted therapy in the treatment of advanced metastatic renal cell carcinoma. Being refractory to conventional hormone therapy, chemotherapy or radiotherapy, renal cell carcinoma has become a model tumor for the development and evaluation of diverse novel targeted drugs. This review highlights currently available agents and summarizes evidence-based data regarding their effectiveness in metastatic renal cell carcinoma. Furthermore, the role of debulking tumor nephrectomy followed by systemic therapy as part of an optimum treatment algorithm is being elucidated.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Combined Modality Therapy; Everolimus; Humans; Indoles; Kidney Neoplasms; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Everolimus (also known as RAD-001; Afinitor®) is an orally active inhibitor of the intracellular protein kinase mammalian target of rapamycin. The U.S. Food and Drug Administration and the European Medicines Agency recently approved everolimus for the treatment of advanced renal cell carcinoma (RCC) on the basis of the results of a randomized phase III clinical trial. In the trial, 10 mg daily everolimus was effective and well tolerated by patients with advanced RCC, whose disease had progressed while under the treatment with sunitinib and/or sorafenib. Everolimus treatment led to 36% of 6-month progression-free survival (PFS) rate and 31% of 3-month PFS rate. Most of the adverse events were mild to moderate (grade 1-2) in severity. The most frequent grade 3-4 adverse events were stomatitis, fatigue, pneumonitis and infections. Clinical trials on everolimus in combination with sunitinib, sorafenib, imatinib and vatalanib for the treatment of RCC are ongoing.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Drug Interactions; Everolimus; Evidence-Based Medicine; Humans; Kidney Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

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

This paper represents a summary of the evidence review group (ERG) report into the clinical efficacy, safety and cost-effectiveness of everolimus plus best supportive care (BSC) for the treatment of advanced renal cell carcinoma (RCC) which has progressed following or on vascular endothelial growth factor-targeted therapy (sunitinib, sorafenib, bevacizumab), compared to BSC alone. The submitting manufacturer's case for clinical effectiveness and cost-effectiveness was mainly based on a well-conducted randomised controlled trial (RCT), Renal Cell Cancer Treatment with Oral RAD001 Given Daily-1 (RECORD-1), comparing BSC plus everolimus with BSC plus placebo and a de novo economic model. The RCT indicated a marked statistically significant effect on progression-free survival. The base-case incremental cost-effectiveness ratio (ICER) estimate was 52,000 pounds per quality-adjusted life-year (this included a reduction in drug cost associated with an approved patient access scheme). The ERG undertook a critical appraisal of the submission. The ERG was generally in agreement with the submitting manufacturer concerning its estimates of effectiveness; however, there was greater concern surrounding the estimates of cost-effectiveness. The ERG judged that if potential errors in the model were corrected, the ICERs offered by the submitting manufacturer would overstate the cost-effectiveness of everolimus for the second-line treatment of metastatic RCC (that this ICER would be a higher value). Concerning the estimates of cost-effectiveness in RCC, the observations in the ERG report provide strong further support for research collecting rigorous estimates of utilities associated with the main health states likely to be experienced by patients with renal cell cancer. At the time of writing, NICE was yet to issue the Appraisal Consultation Document for this appraisal.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cost-Benefit Analysis; England; Everolimus; Humans; Kidney Neoplasms; Randomized Controlled Trials as Topic; Sirolimus; Wales

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 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

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 mammalian target of rapamycin (mTOR) pathway inhibition has emerged as one of the main directions for the development of new targeted agents in renal cell carcinoma (RCC). A prominent member in its class of medications, temsirolimus has already been shown to improve overall survival in advanced kidney cancer, when compared with the previous standard, IFN-alpha.. The aim of this study was to review the most relevant preclinical and clinical data on the mTOR inhibitors, both in clinical use or in current development.. The authors give a comprehensive review of the existing English literature on the role of the mTOR pathway in renal tumorigenesis, as well as a detailed safety and efficacy analysis of older and newer rapamycin analogs.. Rapamycin derivatives temsirolimus and everolimus have significant clinical activity in patients with advanced-stage RCC. Both parenteral and oral formulations of mTOR inhibitors have shown clinical efficacy and are currently being developed. Combinations of mTOR inhibitors with VEGF/VEGFR-blocking agents are also being studied, in an attempt to further enhance the antineoplastic effect.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Hypophosphatemia; Kidney Neoplasms; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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

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

The recent introduction of drugs that inhibit angiogenesis or the mTOR has provided new options for the treatment of metastatic renal cell carcinoma, a disease which often has a poor prognosis. Chemotherapy and cytokine therapy are largely ineffective. The 5-year survival rate is under 10%. Everolimus, an immunosuppressive drug widely used for the prevention of allograft rejection and an mTOR inhibitor, is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma. It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors (sunitinib, sorafenib or both), which interfere with signaling pathways, such as the VEGF pathway. Clinical efficacy results (progression-free survival) for everolimus are promising and the safety profile is good.

Topics: Animals; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Neoplasm Metastasis; Protein Kinases; Sirolimus; Survival Rate; 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

Renal epithelioid angiomyolipomas (ReAML) are rare tumors (identified in less than 0,1 per thousand in general population) and represent 8% of operated angiomolipomas (AML). The diagnostic is histological, with an epithelioid cell component among the typical AML cells. ReAML are tumors derived from perivascular epithelioid cells (PEComa). There are benign PEComas, potentially aggressive PEComas and malignant PEComas. Most malignant PEComas are ReAML. There are two ReAML clinical entities, sporadic or associated to Tuberous Sclerosis Complex (TSC). ReAML are unique, localized and sporadic solid tumors of the kidney of variable size that can be revealed as classical AML with local symptoms or a complication (hemorrhage). Revelation mode is mostly radiologic. ReAML are fat-poor on CT-scan. They can be misdiagnosed with renal cell carcinoma (RCC). (One third of ReAML are malignant with a locoregional, nodal or metastatic evolution that can lead to death. ReAML treatments are multimodal depending of histology, clinical-radiological entity, evolution and the patient. Partial nephrectomy or follow-up are the benign entity treatment. Radical nephrectomy eventually followed by doxorubicine or rapamycine treatments are recommended for potentially aggressive and malignant entities.

Topics: Angiomyolipoma; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Doxorubicin; Humans; Kidney Neoplasms; Nephrectomy; Prognosis; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

The mammalian target of rapamycin(mTOR)and its molecular pathways are supposed to be activated frequently in human renal cell carcinoma as well as other cancers. It has a kinase activity for 40S ribosomal protein kinase and eukaryotic translation initiation factor 4E-binding protein 1. These proteins, when phosphorylated, promote protein translation and RNA transcription in the nutrient-rich condition. mTOR inhibitors such as Temsirolimus (CCI779) and Everolimus (RAD001) are effective for suppressing cell growth with inhibiting mTOR kinase activity. Rapamycin and its related analogs such as Temsirolimus and Everolimus are less toxic for humans compared with other anti-VEGFR inhibitors and has been used as an immunosuppressive agent. These agents have an inhibitory activity against the mTORC1 complex. Since they do not have inhibitory activity against mTORC2 complex, the ability of mTOR inhibition by Temsirolimus is supposed to be 40 to 50% of full inhibition in mTOR kinase. Temsirolimus has modest anticancer activity against advanced clinical RCC patients with poor risk. The objective response rate was only 7%, 26% of patients experienced minor responses and another 17% of patients had stable disease that lasted 6 months. The median time to tumor progression and median survival for the study patients were 5.8 and 15.0 months, respectively. The overall survival of patients treated with Temsirolimus alone was statistically longer than in those treated with IFN alone in the 626 cases in phase II study. Combinations of mTOR with other anti- VEGFR agents were not effective. Vertical therapies of mTOR inhibitor in combination with AKT inhibitors, or newly development of stronger mTOR kinase which can suppress both mTORC1 and mTORC2 are planned at present.

Topics: Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Neoplasm Metastasis; Protein Serine-Threonine Kinases; Sirolimus

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

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

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

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

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

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

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

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

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

Inhibitors of the mammalian target of rapamycin (mTOR) have shown promising efficacy in early-stage trials in patients with advanced renal cell carcinoma (RCC). Most RCCs have been shown to possess biallelic alterations in the von Hippel-Lindau (VHL) gene, resulting in accumulation of hypoxia-inducible factors 1alpha and 2alpha, as well as their downstream targets including vascular endothelial growth factor (VEGF). The observed clinical efficacy of mTOR inhibitors in patients with RCC may be mediated in part by the dependence of efficient hypoxia-inducible factor translation on the mTOR pathway. mTOR inhibitors have entered more advanced phase clinical trials either as single agents or in combination with other targeted agents or IFN, which might ultimately result in regulatory approval of one or more agents. Given the likely nonoverlapping mechanism of action of mTOR inhibitors and VEGF pathway-targeted agents, mTOR inhibitors may prove useful if administered in combination or after resistance to VEGF inhibitors. With an increasing number of active agents for treatment of patients with RCC, efforts must continue to develop patient selection models based on predictive biomarkers to direct therapy to appropriate patients.

Topics: Biomarkers, Tumor; Carcinoma, Renal Cell; Clinical Trials as Topic; Extracellular Signal-Regulated MAP Kinases; Humans; Hypoxia; Interferons; Kidney Neoplasms; Models, Biological; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Vascular Endothelial Growth Factor A

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

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

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

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

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

Kidney cancer, although relatively rare when compared to other malignancies, occurs not uncommonly in patients with renal disease and is often discovered incidentally during the initial nephrologic work-up, or by the savvy clinician who is familiar with the paraneoplastic signs. While surgical approaches are generally curative when the disease is confined to the kidney, one-third of the cases that present in the metastatic form and require conventional medical therapy are associated with a truly dismal patient survival rate. In light of the emerging knowledge of the molecular mechanisms of kidney cancer oncogenesis, several novel and promising therapeutic approaches are emerging. In this review, we summarize the current state of kidney cancer diagnosis and therapy, as well as some of the novel treatments that capitalize on those newly elucidated molecular pathways that are deranged in this disease.

Topics: Animals; Carcinoma, Renal Cell; Cyclin-Dependent Kinase Inhibitor p21; Humans; Hypoxia-Inducible Factor 1; Kidney Neoplasms; Mutation; Protein Kinase Inhibitors; Sirolimus; Von Hippel-Lindau Tumor Suppressor Protein

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

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

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

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Carrier Proteins; Cell Cycle Proteins; Clinical Trials as Topic; Enzyme Inhibitors; G1 Phase; Humans; Insulin-Like Growth Factor I; Kidney Neoplasms; Phosphoproteins; Phosphorylation; Protein Biosynthesis; Protein Kinase Inhibitors; Protein Kinases; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Tacrolimus Binding Protein 1A; TOR Serine-Threonine Kinases

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

Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery.. In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants.. Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo.. Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery.. US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

Topics: Adjuvants, Immunologic; Adult; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Neoplasm Recurrence, Local; Sirolimus; United States

Glutaminase is a key enzyme, which supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects, which translated to encouraging safety and efficacy findings in a phase I trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667).. Eligible patients with mRCC, previously treated with at least two prior lines of therapy [including ≥1 VEGFR-targeted tyrosine kinase inhibitor (TKI)] were randomized 2:1 to receive E, plus Tela or Pbo, until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed progression-free survival (PFS; one-sided α <0.2).. Sixty-nine patients were randomized (46 TelaE, 23 PboE). Patients had a median three prior lines of therapy, including TKIs (100%) and checkpoint inhibitors (88%). At median follow-up of 7.5 months, median PFS was 3.8 months for TelaE versus 1.9 months for PboE [HR, 0.64; 95% confidence interval (CI), 0.34-1.20; one-sided P = 0.079]. One TelaE patient had a partial response and 26 had stable disease (SD). Eleven patients on PboE had SD. Treatment-emergent adverse events included fatigue, anemia, cough, dyspnea, elevated serum creatinine, and diarrhea; grade 3 to 4 events occurred in 74% TelaE patients versus 61% PboE.. TelaE was well tolerated and improved PFS versus PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.

Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Everolimus; Glutaminase; Glutamine; Humans; Kidney Neoplasms; Protein Kinase Inhibitors; Sirolimus

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

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

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

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

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

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

To determine whether 2D or 3D Choi and modified Choi (mChoi) criteria could assess the efficacy of everolimus against metastatic renal cell carcinoma (mRCC).. RECIST-1.1, Choi, and mChoi criteria were applied retrospectively to analyse baseline and 2-month contrast-enhanced computed tomography (CECT) images in 48 patients with mRCC enrolled in the everolimus arm of the French randomized double-blind multicentre phase III trial comparing everolimus versus placebo (RECORD-1). The primary endpoint was centrally reviewed progression-free survival (PFS) calculated from the initial RECORD-1 analysis. Mean attenuation was determined for 2D target lesion regions of interest drawn on CECT sections whose largest diameters had been measured, and for the 3D whole target lesion.. The median PFS was 5.5 months. The median PFS for everolimus responders defined using 3D mChoi criteria was significantly longer than for non-responders (7.6 versus 5.4 months, respectively), corresponding to a hazard ratio for progression of 0.45 (95 % CI: 0.22-0.92), with respective 1-year survival rates of 31 % and 9 %. No other 2D or 3D imaging criteria at 2 months identified patients who would benefit from everolimus.. At 2 months, only 3D mChoi criteria were able to identify mRCC patients with a PFS benefit from everolimus.. Choi criteria could not identify everolimus-treated patients with significantly prolonged PFS. mCHOI enabled identification of everolimus-treated mRCC patients with a PFS benefit. 3D attenuation measurement criteria appeared to perform better than single-slice measurement.

Topics: Adult; Aged; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Everolimus; Female; France; Humans; Imaging, Three-Dimensional; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Retrospective Studies; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases; Treatment Outcome

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

Bone metastases from renal cell carcinoma (RCC) are a major cause of morbidity. Post hoc analysis has suggested that bone turnover markers can identify patients at risk of skeletal-related events (SREs) among those receiving zoledronic acid. This study sought to evaluate the effect on bone metastases of everolimus alone compared with everolimus plus zoledronic acid.. Thirty treatment-naive patients with RCC and ≥ 1 bone metastases were randomized 1:1 to everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4-weekly). Bone-specific assessments were performed at baseline and at weeks 1, 4, 8, and 12. Treatment was continued on allocated arm until progression per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1). The primary outcome measure was urine N-telopeptide (uNTX) level, with secondary measures of plasma C-telopeptide (CTX), quality of life (Functional Assessment of Cancer Therapy-Bone Pain [FACT-BP], Brief Pain Inventory [BPI]), progression-free survival (PFS), SREs, and safety.. After 12 weeks, reduction in mean uNTX and CTX on everolimus plus zoledronic acid relative to everolimus was 68.4% (95% CI, 60.1%-74.9%; P < .0001) and 76.2% (95% CI, 67.3%-82.7%; P < .0001), respectively. There was no evidence of a difference for FACT-BP (P = .5), but evidence was favorable for BPI Severity (P = .05) and BPI Interference (P = .06). Median PFS was 7.5 months (95% CI, 3.4-11.2) on everolimus plus zoledronic acid and 5.4 months (95% CI, 3.2-6.3) on everolimus (P = .009). Median time to first SRE was 9.6 months (95% CI, 4.3-15.5) on everolimus plus zoledronic acid and 5.2 months (95% CI, 1.6-8.2) on everolimus (P = .03).. In this RCC population, the addition of zoledronic acid to everolimus significantly reduced bone resorption markers and may prolong tumor control.

Topics: Aged; Antineoplastic Agents; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma, Renal Cell; Collagen Type I; Diphosphonates; Everolimus; Female; Humans; Imidazoles; Kidney Neoplasms; Male; Middle Aged; Peptides; Prospective Studies; Sirolimus; Treatment Outcome; Zoledronic Acid

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

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

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

Drugs inhibiting the mammalian target of rapamycin (mTOR) are approved in the treatment of renal cell carcinoma (RCC), but resistance inevitably emerges. Proposed escape pathways include increased phosphorylation of Akt, which can be down regulated by histone deacetylase (HDAC) inhibitors. We hypothesized that co-treatment with the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat may abrogate resistance in RCC.. This phase 1 study evaluated the co-administration of ridaforolimus and vorinostat in patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD) in RCC patients. Although all solid tumors were allowed, prior cytotoxic chemotherapy was limited to 1 regimen. Using a modified 3 + 3 dose escalation design, various dose combinations were tested concurrently in separate cohorts. Efficacy was a secondary endpoint.. Fifteen patients were treated at one of three dose levels, thirteen with RCC (10 clear cell, 3 papillary). Dosing was limited by thrombocytopenia. The MTD was determined to be ridaforolimus 20 mg daily days 1-5 with vorinostat 100 mg BID days 1-3 weekly, however late onset thrombocytopenia led to a lower recommended phase II dose: ridaforolimus 20 mg daily days 1-5 with vorinostat 100 mg daily days 1-3 weekly. Two patients, both with papillary RCC, maintained disease control for 54 and 80 weeks, respectively.. The combination of ridaforolimus and vorinostat was tolerable at the recommended phase II dose. Two patients with papillary RCC experienced prolonged disease stabilization, thus further study of combined HDAC and mTOR inhibition in this population is warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Sirolimus; TOR Serine-Threonine Kinases; Vorinostat

Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.. A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.. The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).. Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Quality of Life; Sirolimus; Survival Analysis; Young Adult

Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.. We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate.. Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.. Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Pyridines; Quality of Life; Sirolimus; Survival Analysis

Response Evaluation Criteria in Solid Tumors (RECIST) criteria may not be sufficient to evaluate the response of targeted therapies in metastatic renal cell carcinoma (mRCC). The tumor growth rate (TGR) incorporates the time between evaluations and may be adequate.. To determine how TGR is modified along the treatment sequence and is associated with outcome in mRCC patients.. Medical records from all patients prospectively treated at Gustave Roussy (IGR) in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) (sorafenib vs placebo, n=84) and the RECORD (everolimus vs placebo, n=43) phase 3 trials were analyzed. TGR was computed across clinically relevant periods: BEFORE treatment introduction (wash-out), UNDER (first cycle), at PROGRESSION (last cycle) and AFTER treatment discontinuation (washout). The association between TGR and outcome (overall survival [OS] and progression-free survival [PFS]) was computed in the entire TARGET cohort (n=903).. Sorafenib, everolimus, or placebo.. TGR, RECIST, OS, and PFS rates.. Although nearly all the patients (IGR) were classified as stable disease (RECIST) after the first cycle, the great majority of the patients exhibited a decrease in TGR UNDER compared with BEFORE (sorafenib: p<0.00001; everolimus: p<0.00001). In sorafenib-treated but not in everolimus-treated patients (IGR), TGR at PROGRESSION (last cycle) was still lower than TGR BEFORE (washout) (p=0.012), while TGR AFTER progression (washout) was higher than TGR at PROGRESSION (last cycle) (p=0.0012). Higher TGR (first cycle) was associated with worse PFS (hazard ratio [HR]: 3.61; 95% confidence interval [CI], 2.45-5.34) and worse OS (HR: 4.69; 95% CI, 1.54-14.39), independently from the Motzer score and from the treatment arm in the entire TARGET cohort.. Computing TGR in mRCC patients is simple and provides clinically useful information for mRCC patients: (1) TGR is independently associated with prognosis (PFS, OS), (2) TGR allows for a subtle and quantitative characterization of drug activity at the first evaluation, and (3) TGR reveals clear drug-specific profiles at progression.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prospective Studies; Sirolimus; Sorafenib; Time Factors; Treatment Outcome; Tumor Burden

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

Lenvatinib is an oral multi-targeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRβ, RET, and KIT. Everolimus is an oral mammalian target of rapamycin inhibitor approved for advanced renal cell carcinoma (RCC). This phase 1b study assessed safety, maximum tolerated dose (MTD), and preliminary antitumor activity of lenvatinib plus everolimus in metastatic RCC (mRCC) patients.. Patients with advanced unresectable or mRCC and Eastern Cooperative Oncology Group performance status 0-1 were eligible (number of prior treatments not restricted). Starting dose was lenvatinib 12 mg once daily with everolimus 5 mg once daily administered continuously in 28-day cycles using a conventional 3 + 3 dose-escalation design. At the MTD, additional patients were enrolled in an expansion cohort.. Twenty patients (mean 58.4 years) received lenvatinib [12 mg (n = 7); 18 mg (n = 11); 24 mg (n = 2)] plus everolimus 5 mg. MTD was established as once daily lenvatinib 18 mg plus everolimus 5 mg. The most common treatment-related treatment-emergent adverse events (all dosing cohorts) were fatigue 60 % (Grade ≥3: 10 %), mucosal inflammation 50 %, proteinuria (Grade ≥3: 15 %), diarrhea (Grade ≥3: 10 %), vomiting (Grade ≥3: 5 %), hypertension, and nausea, each 40 %. In MTD and lowest-dose cohorts (n = 18), best responses of partial response and stable disease were achieved in 6 (33 %) and 9 (50 %) patients, respectively.. Lenvatinib 18 mg combined with everolimus 5 mg was associated with manageable toxicity consistent with individual agents and no new safety signals. Observed activity warrants further evaluation of the combination in advanced RCC patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Phenylurea Compounds; Quinolines; Sirolimus

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

The mTOR inhibitor, everolimus, is approved for the treatment of metastatic renal cell carcinoma (RCC). However, prognostic models are needed to determine the patients who would most benefit from this therapy. We have developed a model based on clinical parameters and patient stratification into risk groups to predict patients with RCC who will derive the most benefit from treatment with everolimus.. We assessed retrospective data on 57 patients with RCC who received everolimus after previous treatment with immunotherapy or tyrosine kinase inhibitors to identify prognostic factors for progression-free survival (PFS) and overall survival (OS). In the original phase II study, patients received 10mg of everolimus daily without interruption and were assessed every other week for the first 8 weeks on therapy and every 4 weeks thereafter. Kaplan-Meier analysis was used to calculate OS and PFS. Univariate and multivariate analyses were constructed using the Cox proportional hazards model and a stepwise procedure to validate the data.. We grouped patients according to risk: 0 prognostic factors indicated favorable risk, 1 to 2 factors intermediate risk, and≥3 factors poor risk. We found notable differences in median OS (29.6 mo for favorable risk, 14.3 mo for intermediate risk, and 7.2 mo for poor risk). Three risk factors (prior radiation treatment, no lung metastasis present at the start of treatment, and lymphocytes<25cells/µl) in the multivariate analysis were found to be associated with PFS, and 4 risk factors were found to be associated with OS (bone metastasis at start of treatment, LDH>1.5×upper limit of normal, alkaline phosphatase>120U/l, and lymphocytes<25cells/µl).. Our prognostic model includes 3 readily available clinical parameters for PFS and 4 readily available clinical parameters for OS to help stratify patients into poor, intermediate, and favorable prognosis groups for the treatment of everolimus in clear cell RCC. These intriguing results warrant further study in a larger patient population to validate the findings.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Prognosis; Proportional Hazards Models; Protein Kinase Inhibitors; Sirolimus

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

Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC).. A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC.. We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients.. Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Phthalazines; Prognosis; Protein Kinase Inhibitors; Pyridines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases

Tuberous sclerosis complex (TSC) is characterized by benign tumours in multiple organs, including the brain, kidneys, skin, lungs and heart. Our objective was to evaluate everolimus, an mTOR inhibitor, in the treatment of angiomyolipoma in patients with subependymal giant cell astrocytoma (SEGA) associated with TSC.. EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (NCT00789828), a prospective, double-blind, randomized, placebo-controlled, Phase 3 study, examined everolimus in treating SEGA associated with TSC. Patients with serial SEGA growth from pre-baseline to baseline scans were randomly assigned (2:1) to receive 4.5 mg/m(2)/day everolimus (target blood trough: 5-15 ng/mL; n = 78) or placebo (n = 39). Angiomyolipoma response rates were analysed in patients (n = 44) with target baseline angiomyolipoma lesions (≥1 angiomyolipoma; longest diameter ≥1.0 cm). An angiomyolipoma response rate, defined as the proportion of patients with confirmed angiomyolipoma response, was assessed by kidney CT or MRI screening at baseline, at 12, 24 and 48 weeks and annually.. Angiomyolipoma response rates were 53.3% (16/30) and 0% (0/14) for everolimus- and placebo-treated patients, respectively. Angiomyolipoma reductions ≥50% in the sum of volumes of all target lesions were seen only in everolimus-treated patients (56.5, 78.3 and 80.0%) compared with placebo-treated patients (0% at each time point) at Weeks 12, 24 and 48, respectively. Greater percentages of everolimus-treated patients had angiomyolipoma reductions ≥30% at these same time points (82.6, 100 and 100% versus 8.3, 18.2 and 16.7% for everolimus versus placebo, respectively).. Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.The trial is registered with ClinicalTrials.gov, number NCT00789828; http://clinicaltrials.gov/ct2/show/NCT00789828?term=EXIST-1&rank=1.

Topics: Adult; Angiomyolipoma; Antineoplastic Agents; Astrocytoma; Brain; Child, Preschool; Double-Blind Method; Everolimus; Female; Humans; Kidney Neoplasms; Male; Neoplasms, Multiple Primary; Prospective Studies; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome; Tuberous Sclerosis

Everolimus (mammalian target of rapmaycin (mTOR) inhibitor) and dovitinib (vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. The combination is explored in this phase Ib study.. Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalating doses of everolimus and dovitinib. Dose-limiting toxicities (DLTs) were assessed to determine the maximum tolerated dose (MTD). An expansion cohort (n=15) was investigated to obtain additional efficacy information. Sequential fluorodeoxyglucose positron emission tomography (FDG-PET) was used as a surrogate marker of response.. Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5mg orally (PO) once daily (OD) and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (Common Toxicity Criteria (CTC) grade 1-4) of patients, respectively. Frequent biochemical abnormalities occurred (such as hypertriglyceridaemia in 67%). Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% confidence interval (CI) 2.2-11 months). Pharmacokinetic data at the MTD showed stable kinetics with time.. Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Renal Cell; Cohort Studies; Disease-Free Survival; Dose-Response Relationship, Drug; Everolimus; Fatigue; Female; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Quinolones; Sirolimus

A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma.. RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end points included combined PFS for each sequence, overall survival (OS), and safety.. Of 471 enrolled patients, 238 were randomly assigned to first-line everolimus followed by sunitinib, and 233 were randomly assigned to first-line sunitinib followed by everolimus. The primary end point was not met; the median PFS was 7.9 months for first-line everolimus and 10.7 months for first-line sunitinib (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.8). Among patients who discontinued first-line, 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus. The median combined PFS was 21.1 months for sequential everolimus then sunitinib and was 25.8 months for sequential sunitinib then everolimus (HR, 1.3; 95% CI, 0.9 to 1.7). The median OS was 22.4 months for sequential everolimus and then sunitinib and 32.0 months for sequential sunitinib and then everolimus (HR, 1.2; 95% CI, 0.9 to 1.6). Common treatment-emergent adverse events during first-line everolimus or sunitinib were stomatitis (53% and 57%, respectively), fatigue (45% and 51%, respectively), and diarrhea (38% and 57%, respectively).. Everolimus did not demonstrate noninferiority compared with sunitinib as a first-line therapy. The trial results support the standard treatment paradigm of first-line sunitinib followed by everolimus at progression.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cross-Over Studies; Disease-Free Survival; Drug Administration Schedule; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrroles; Sirolimus; Sunitinib; Treatment Outcome; Young Adult

Topics: Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Neoplasm Metastasis; Prognosis; Pyrroles; Risk Assessment; Sirolimus; Sunitinib; Survival Analysis; Time Factors; Treatment Outcome

We have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up.. To compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS). DESIGN AND INTERVENTION(S): Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0-12 months. During months 12-24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus.. Adult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1).. There were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients.. We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups.. At 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787 ± 426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971 ± 4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p=0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed.. Clinical trials.gov NCT00126672.

Topics: Adult; Angiomyolipoma; Female; Humans; Kidney; Kidney Neoplasms; Male; Sirolimus; Time Factors; Tuberous Sclerosis; Vascular Endothelial Growth Factor D

Everolimus is approved for treatment of anti-vascular endothelial growth factor (VEGF)-refractory patients with metastatic renal cell carcinoma (mRCC). Clinical trials rarely mirror treatment reality. Thus, a broader evaluation of everolimus is valuable for routine use.. A German multicenter non-interventional study documented mRCC patients starting everolimus after failure of initial VEGF-targeted therapy. Primary endpoint was effectiveness, defined as time to progression (TTP) according to investigator assessment (time from first dose to progression).. Of 382 documented patients, 196 were included in this interim analysis. In the efficacy population (n = 165), median TTP was 7.0 months (95% confidence interval (CI) 5.1-9.0). Among patients with < or ≥ 6 months of previous VEGF-targeted therapy, median TTP was 6.6 months (95% CI 3.8-not estimable) and 7.4 months (95% CI 4.6-9.6), respectively. Most common adverse events were anemia (13%) and dyspnea (14%). Physicians assessed high tolerance and documented high adherence to everolimus therapy (approximately 97%).. In routine clinical practice, everolimus is effective, as measured by median TTP (longer than median progression-free survival in RECORD-1 trial), and well tolerated. Our results support everolimus use in anti-VEGF-refractory patients with mRCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Everolimus; Female; Germany; Humans; Kidney Neoplasms; Male; Middle Aged; Prevalence; Protein-Tyrosine Kinases; Receptors, Vascular Endothelial Growth Factor; Risk Assessment; Sirolimus; Treatment Failure; Treatment Outcome; Young Adult

In China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC.. An open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011.. A total of 64 patients were included in the study. Median age was 52 years (range, 19-75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response.. Safety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical benefit to Chinese patients with anti-VEGF-refractory mRCC.. clinicaltrials.gov, NCT01152801.

Topics: Adult; Aged; Antineoplastic Agents; Asian People; Carcinoma, Renal Cell; China; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Treatment Outcome; Young Adult

To evaluate the feasibility and efficacy of sorafenib and everolimus in renal cell carcinoma (RCC).. Patients with advanced RCC and ≤ 1 previous targeted therapy were treated.. Maximum tolerated doses were sorafenib 200 mg PO BID, everolimus 35 mg PO once weekly. Dose-limiting toxicity was hand-foot syndrome. The response rate was 13%; median PFS was 5.45 months (95% CI: 3.8-7.6). Skin toxicity, fatigue, hypertension, proteinuria, and mucositis (usually Grade 2) were common.. Fifty percent doses of sorafenib and everolimus were required when these drugs were combined. No increase in efficacy was suggested; toxicity was modestly increased.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Hand-Foot Syndrome; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Niacinamide; Phenylurea Compounds; Sirolimus; Sorafenib; Treatment Outcome

This phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma.. Fifty-five patients with metastatic clear cell renal carcinoma who had previously received first-line treatment with sunitinib (39 patients) or bevacizumab (16 patients) were enrolled. Patients received pazopanib 800 mg orally daily and were evaluated for response after 8 weeks of treatment. Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and confirmed with repeated scans after 8 weeks. Patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred.. Fifteen of 55 patients (27%) had objective response to pazopanib. An additional 27 patients (49%) had stable disease, for a disease control rate of 76%. After a median follow-up of 16.7 months, the median progression-free survival for the entire group was 7.5 months (95% confidence interval, 5.4-9.4 months). Similar progression-free survival was observed regardless of whether previous treatment was with sunitinib or bevacizumab. The estimated overall survival rate for the entire group at 24 months was 43%.. Pazopanib is an active agent for the treatment of advanced clear cell renal carcinoma, even after failure of sunitinib or bevacizumab. Treatment with pazopanib should be considered early in the sequence of therapy for patients with advanced renal cell carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; Sunitinib; Treatment Outcome

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

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

The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([(18)F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37-80). Median pre- and 2-week treatment average SUVmax were 6.6 (1-17.9) and 4.2 (1-13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (-32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers; Carcinoma, Renal Cell; Everolimus; Female; Fluorodeoxyglucose F18; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Positron-Emission Tomography; Sirolimus; Treatment Outcome; Tumor Burden

An emerging literature describes the potential for long-term survival with targeted agents, but the health-related quality of life (HR-QOL) in patients who receive chronic therapy with these agents is poorly defined.. From an institutional database including 562 patients with renal cell carcinoma (RCC), patients were identified who (1) were alive 3 years beyond initiation of systemic therapy for metastatic renal cell carcinoma (mRCC) and (2) received a targeted therapy as a component of their treatment. European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 36 (QLQ-C30) and Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-15) questionnaires were administered by telephone survey. Data from questionnaires were compared with historical estimates derived from pivotal studies evaluating targeted agents.. A total of 38 patients met eligibility criteria for the study, and 28 patients participated in the telephone survey. Most were male patients and had clear cell histologic type (75% for both). All patients had either good- or intermediate-risk disease by Heng criteria. The mean QLQ-C30 Global QOL score in the present cohort was higher than the mean score among patients evaluated at baseline in the phase III evaluations of pazopanib (73.5 vs. 65.8; P = .07) and everolimus (73.5 vs. 61.0; P = .007). The FKSI-15 score in the present cohort was similar to the mean score among patients evaluated at baseline in the phase III evaluation of sunitinib (45.1 and 46.5, respectively; P = .41).. In this small pilot study, long-term survivors with mRCC who received targeted therapies appear to have an HR-QOL comparable to that of patients who participated in relevant phase III studies. Given the many emerging treatment options for mRCC, the HR-QOL of long-term survivors warrants greater attention.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunosuppressive Agents; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pilot Projects; Pyrimidines; Quality of Life; Sirolimus; Sulfonamides; Surveys and Questionnaires; Survivors; Treatment Outcome

We investigated the efficacy of everolimus against nonclear-cell renal cell carcinoma (nccRCC). Patients and methods Patients with nccRCC received 10-mg everolimus once daily until disease progression or unacceptable toxicity.. who had received a VEGF- tyrosine kinase inhibitor (TKI) previously were included.. A total of 49 patients were enrolled. Twenty-three patients (46.9%) received prior anti-VEGF agents. A partial response was observed in five patients (10.2%) and stable disease in 25 patients (51.0%). The disease progressed in 16 patients (32.7%) despite the administration of everolimus. Two of the five patients who showed an objective response to everolimus had chromophobe carcinoma, whereas two had papillary carcinoma and one had unclassifiable carcinoma. Thirty-six patients experienced disease progression during follow-up, and the median progression-free survival (PFS) was 5.2 months. Chromophobe RCC patients seemed to have longer PFS than nccRCC patients with the other histological subtypes (P = 0.084). Previous VEGF-TKI treatment did not influence the efficacy of everolimus, and the toxicity profiles were in line with previous reports.. Everolimus shows certain efficacy against nccRCC, particularly in patients with chromophobe RCC, and prior treatment with a VEGF-TKI appears not influencing the outcome of everolimus therapy in nccRCC patients. ClinicalTrials.gov number NCT00830895.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

The phase 3 RECORD-1 study demonstrated clinical benefit of everolimus over placebo (median progression-free survival: 4.9 mo compared with 1.9 mo, p<0.001) in treatment-resistant patients with metastatic renal cell carcinoma (mRCC). However, the Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate was low.. To explore the potential role of tumor burden response to everolimus in predicting patient survival.. RECORD-1 patients with at least two tumor assessments (baseline and weeks 2-14) were included (n=246).. A multivariate Cox proportional hazard model was used to assess the impact of various prognostic factors on overall survival (OS). Components of RECIST progression were explored using univariate Cox regression.. The baseline sum of longest tumor diameters (SLD) and progression at weeks 2-14 were prognostic factors of OS by multivariate analysis. Univariate analysis at weeks 2-14 demonstrated that growth of nontarget lesions and appearance of new lesions were predictive of OS (p<0.001). This retrospective analysis used data from one arm of one trial; patients in the placebo arm were excluded because of confounding effects when they crossed over to everolimus.. This analysis identified baseline SLD as a predictive factor of OS, and the appearance of a new lesion or progression of a nontarget lesion at first assessment after baseline also affects OS in patients with mRCC treated with everolimus.

Topics: Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Neoplasm Metastasis; Prognosis; Retrospective Studies; Sirolimus; Survival Rate; Tumor Burden

To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program.. Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors.. The study stratified 1367 evaluable patients into treatment duration groups of <3 months, ≥3 and <6 months, ≥6 months and <1 year, and ≥1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for ≥1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of ≥6 months was associated with improved disease control rates.. Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations≥1 year and not associated with cumulative toxicity.

Topics: Aged; Anemia; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Dyspnea; Everolimus; Fatigue; Female; Humans; Hyperglycemia; Kidney Neoplasms; Male; Middle Aged; Pneumonia; Sirolimus; Stomatitis; Time Factors; Treatment Outcome

Because the response to treatment is limited, patients with metastatic renal cell carcinoma (mRCC) typically receive multiple treatments. Guidelines recommend everolimus for patients previously treated with tyrosine kinase inhibitors (TKI) sunitinib or sorafenib. This study evaluated the efficacy of TKI re-treatment in patients with disease progression after a TKI-everolimus sequence.. Data were reviewed for patients enrolled in RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) at French sites. Response, progression-free survival (PFS), and overall survival were evaluated in patients treated with a TKI-everolimus-TKI sequence.. Thirty-six patients received a TKI after everolimus: sunitinib in 17 patients, sorafenib in 15, and dovitinib (TKI258) in 4. The response rate with TKI re-treatment was 8%, and the disease-control rate (response plus stable disease) was 75%. The median PFS with each component of the TKI-everolimus-TKI sequence was 10.7 months (95% CI, 1.8-28.5 months), 8.9 months (95% CI, 1.7-34.6 months), and 8.2 months (95% CI, 5.2-11.9 months), respectively. The median overall survival from the start of everolimus was 29.1 months (95% CI 21.1 to not reached months), which suggests a benefit in using TKI in this setting.. Administration of a TKI-everolimus-TKI sequence may be associated with clinical benefit and should be prospectively investigated.

Topics: Adult; Aged; Antineoplastic Agents; Benzimidazoles; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; France; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrroles; Quinolones; Salvage Therapy; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Treatment Failure; Treatment Outcome

Agents that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in metastatic renal cell carcinoma (mRCC) prolong progression-free survival (PFS), but durable complete responses are rare. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but supra-additive toxicity is a valid concern. We investigated whether horizontal blockade with the combination of bevacizumab, a monoclonal antibody to VEGF-A, and of everolimus, an oral mTOR inhibitor, improved PFS in patients with clear cell mRCC who had received prior VEGF blockade.. In this phase II investigator-initiated study, 10 of 30 planned patients were enrolled. Bevacizumab 10 mg/kg was administered intravenously every 14 days. Everolimus was orally dosed at 10 mg daily. The patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS.. The median age was 55 years. The majority of patients were white men with an Eastern Cooperative Oncology Group performance status of 1 (80%) and intermediate risk disease by Memorial Sloan-Kettering Cancer Center criteria (70%). All the patients had received 1 prior VEGF inhibitor. The median PFS in the 10 evaluable patients was 5.1 months, which was less than the expected historical control of bevacizumab monotherapy at 6 months. The median overall survival was 21 months. The best response was a partial response in 1 patient and stable disease in 9. Forty percent of the patients were discontinued from the study due to toxicity.. In our experience, the combination of bevacizumab and everolimus was toxic. The efficacy achieved did not support its combined use over sequential administration. Ongoing randomized studies will definitively evaluate the combination's efficacy and tolerability.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC.. REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter.. A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks.. Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Treatment Failure; Young Adult

Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC.. Sequential cohorts of 3 to 6 patients with advanced RCC received dose-escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained.. Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed.. The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Pyrroles; Sirolimus; Sunitinib

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, and sorafenib, a RAF kinase inhibitor, has shown efficacy in renal cell cancer (RCC) as single agents. We conducted a phase I study to evaluate the maximum tolerated dose (MTD) of combining these agents for potential additive or synergistic effects when treating progressive metastatic RCC (mRCC).. The 15 patients enrolled in the study had predominantly clear cell RCC (cRCC) and progressive measurable disease with previous treatment that included immunotherapy, tyrosine kinase inhibitors, and/or everolimus. Patients received daily everolimus and twice-daily sorafenib at escalating dose levels of 2.5 mg/400 mg (cohort 1), 5 mg/400 mg (cohort 2), and 10 mg/400 mg (cohort 3), and they were evaluated weekly for toxicity and every 8 weeks for response, using computed tomography/positron emission tomography (CT/PET) and CT at baseline and at first staging.. In cohort 1, 2 of 6 patients experienced dose-limited toxicity (DLT) of thrombocytopenia/leukopenia and pneumonitis. In cohort 2, 1 of 6 patients experienced a DLT of pulmonary embolism, and the 3 patients in cohort 3 experienced no DLTs. The MTD was 10 mg/400 mg. Common adverse events included grade 1/2 hand-foot syndrome. Using Response Evaluation Criteria in Solid Tumors (RECIST), 1 patient achieved a pathologic complete response (CR), 1 patient achieved a radiographic CR, and 1 patient achieved a surgical CR. Seven patients achieved stable disease; 10 patients had decreased fluorine-18 fluorodeoxyglucose uptake. Median progressive-free survival was 5.6 months; overall survival was 7.9 months.. The MTD of daily everolimus 10 mg and twice-daily sorafenib 400 mg is safe and effective for progressive mRCC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Everolimus; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Niacinamide; Phenylurea Compounds; Pyridines; Sirolimus; Sorafenib; Treatment Outcome

In the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10mg once daily (n=277) or placebo (n=139). Median progression-free survival (PFS) was 4.9months with everolimus and 1.9months with placebo (hazard ratio [HR], 0.33; P<.001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs.. Median PFS was estimated using the Kaplan-Meier method, and Cox proportional hazards model was used to analyse differences in PFS.. All patients (100%) received ⩾1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr-TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4months with everolimus and 1.9months with placebo (HR, 0.32; 95%confidence interval [CI], 0.24-0.43; P<.001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0months with everolimus and 1.8months with placebo (HR, 0.32; 95%CI, 0.19-0.54; P<.001). The everolimus safety profile was similar for both groups.. Everolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy.

Topics: Adult; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Everolimus; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Proportional Hazards Models; Prospective Studies; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Young Adult

Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.. To evaluate the efficacy and safety of everolimus in elderly patients (those ≥ 65 and ≥ 70 yr of age) enrolled in RECORD-1.. The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n=416).. Everolimus 10mg once daily (n=277) or placebo (n=139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.. Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.. In RECORD-1, 36.8% of patients were ≥ 65 yr and 17.5% were ≥ 70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.. Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Europe; Everolimus; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Molecular Targeted Therapy; Protein Kinase Inhibitors; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome; United States

Objective response as determined by Response Evaluation Criteria in Solid Tumors (RECIST) is low among patients with metastatic renal cell carcinoma (mRCC) treated with targeted agents, despite significantly improved progression-free survival (PFS). A modified response threshold may be more clinically meaningful than RECIST for identifying patients who may derive a PFS benefit from targeted therapy.. We performed a retrospective analysis of data from the phase III RECORD-1 trial of everolimus versus placebo in patients with mRCC who had failed sunitinib or sorafenib (ClinicalTrials.gov identifier: NCT00410124). A series of tumour response thresholds, defined by the best change in the sum of the longest tumour diameters (ΔSLD) of target lesions, was evaluated to distinguish 'responders' from 'non-responders' with respect to significant improvement in PFS.. The optimal threshold for determining a response to everolimus was -5% ΔSLD. At this threshold, median PFS was 8.4 months in responders and 5.0 months in non-responders (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.6-3.7).. In patients who have failed vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy, everolimus affords superior PFS to placebo, regardless of change in tumour burden. However, a ≥ 5% reduction in SLD is a better predictor of PFS benefit than the classical ≥ 30% reduction used with RECIST.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Proportional Hazards Models; Retrospective Studies; ROC Curve; Sensitivity and Specificity; Sirolimus; Time Factors; Treatment Outcome

A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity.. Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan-Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model.. In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations.. Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Double-Blind Method; Everolimus; Female; Humans; Immunosuppressive Agents; International Agencies; Kidney Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Salvage Therapy; Sirolimus; Survival Rate; Treatment Outcome

The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose-response relationship of everolimus.. The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% ± 98.3%, +22.4% ± 17.2%, and -15.7% ± 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time.. In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose-response relationship.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Computer Simulation; Dose-Response Relationship, Drug; Double-Blind Method; Everolimus; Humans; Kidney Neoplasms; Models, Biological; Nonlinear Dynamics; Placebos; Retrospective Studies; Sirolimus

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

Clinical trials in oncology often allow patients randomized to placebo to cross over to the active treatment arm after disease progression, leading to underestimation of the treatment effect on overall survival as per the intention-to-treat analysis. We illustrate the statistical aspects and practical use of the rank-preserving structural failure time (RPSFT) model with the Fleming-Harrington family of tests to estimate the crossover-corrected treatment effect, and to assess its sensitivity to various weighting schemes in the RECORD-1 trial. The results suggest that the benefit demonstrated in progression-free survival is likely to translate into a robust overall survival benefit.

Topics: Algorithms; Antineoplastic Agents; Carcinoma, Renal Cell; Cross-Over Studies; Data Interpretation, Statistical; Double-Blind Method; Everolimus; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Models, Statistical; Models, Structural; Neoplasm Metastasis; Sirolimus; Treatment Failure

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

This phase II study evaluated the activity of combined treatment with the mTOR inhibitor everolimus and the PDGFR inhibitor imatinib in patients with previously-treated, advanced renal carcinoma. The primary endpoint was estimation of the 3-month progression-free rate.. Eligible patients had metastatic or unresectable clear cell renal carcinoma, at least one prior systemic therapy, no prior mTOR inhibitor therapy, performance status 0-2, and measurable disease. Treatment consisted of everolimus 2.5 mg p.o. daily and imatinib 600 mg p.o. daily. The primary endpoint was the 3-month progression-free rate.. The study was closed after the first 19 patients because of an insufficient number of patients who were progression-free at 3 months. The 3-month progression-free rate was 49% (95% C.I. 23%, 72%) and the median progression-free survival was 2.9 months (95% C.I. 1.9, 6.2). Toxicities with an incidence of >  50% included nausea, elevated serum creatinine, edema, anemia, hypocalcemia, fatigue, diarrhea, vomiting, and dyspnea, and leukopenia.. The combination of everolimus with imatinib in previously treated patients with advanced renal carcinoma did not result in a sufficient 3-month progression-free rate to warrant further investigation of this combination.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Everolimus; Female; Humans; Imatinib Mesylate; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Piperazines; Pyrimidines; Sirolimus; Survival Analysis; Treatment Outcome

To assess the efficacy and safety of everolimus in Japanese patients with metastatic renal cell carcinoma.. A subgroup analysis of the pivotal Phase III, randomized, double-blind, placebo-controlled trial of everolimus 10 mg/day in patients with disease progression after treatment with sorafenib, sunitinib or both assessed outcomes in Japanese participants. Results were compared with those for the overall study population.. The final trial analysis included 24 Japanese patients (everolimus, n= 15; placebo, n = 9). Median progression-free survival in the Japanese subpopulation was 5.75 months (95% confidence interval, 4.90 months to not reached) with everolimus and 3.61 months (95% confidence interval, 1.91-9.03 months) with placebo (hazard ratio, 0.19; 95% confidence interval, 0.05-0.83). Median overall survival was not reached with everolimus and was 14.9 months (95% confidence interval, 11.0-16.8 months) with placebo (hazard ratio, 0.30; 95% confidence interval, 0.07-1.27). Overall, efficacy and safety were similar when comparing the Japanese and overall populations. In the Japanese subpopulation, the most common adverse events with everolimus were stomatitis, infections and rash. Four Japanese subjects (27%) developed Grade 1 (n = 2) or 2 (n = 2) pneumonitis (all reversible and allowing for continuation of therapy, after interruption, steroids and dose reduction for both Grade 2 cases), with a lower pneumonitis incidence of 14% in the overall population (albeit associated with a Grade 3 incidence of 4%).. These findings suggest that the demonstrated benefits of everolimus in the overall trial population are similar in Japanese patients with metastatic renal cell carcinoma.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Everolimus; Female; Humans; Immunosuppressive Agents; Incidence; International Cooperation; Japan; Kidney Neoplasms; Male; Middle Aged; Odds Ratio; Pneumonia; Prospective Studies; Sirolimus; Treatment Outcome

The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma.. Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined.. Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib.. The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Sirolimus; Sorafenib; TOR Serine-Threonine Kinases

We performed a single institution, phase I study of sirolimus and bevacizumab, in order to determine the dose limiting toxicity (DLT) and recommended phase II doses.. Eligible patients had previously treated advanced malignancies and were enrolled in three cohorts. Sirolimus 90 mg PO weekly (45 mg on days 1 and 2) was combined with bevacizumab 7.5mg/kg (cohort #1) or bevacizumab 15 mg/kg (cohort #2) IV q3weeks. Sirolimus 4 mg PO daily was combined with bevacizumab 15 mg/kg IV q3weeks (cohort #3).. Twenty-eight patients enrolled. The most common tumour types were colorectal (21%), head/neck (14%), and renal cell (11%). No DLTs were observed in cohorts #1 (4 patients) and #2 (12 patients), while two DLTs (grade 3 confusion and grade 3 fatigue) were observed in the first six patients in cohort #3 (12 patients). The most common grade 3 toxicities were fatigue (18%), hypertension (14%) and anorexia (11%). There were no responses, but one patient has had stable disease for 78 weeks.. The combination of sirolimus and bevacizumab at full doses is tolerable in the majority of patients. The availability and cost of sirolimus compared with other mTOR inhibitors make this an attractive agent to combine with bevacizumab.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Cohort Studies; Colorectal Neoplasms; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

A phase III, randomized, double-blind, placebo-controlled trial was conducted in patients with metastatic renal cell carcinoma. The focus of this paper is to evaluate the patient-reported outcomes.. Patients were randomly assigned (2:1) to receive oral everolimus 10 mg once daily or placebo. The Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS) and European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 were administered before randomization and on day 1 of each cycle. The FKSI-DRS and the EORTC QLQ-C30 Physical Functioning and Global Quality of Life scores were the primary endpoints examined. Longitudinal models were used to compare treatment arms. Sensitivity analyses were conducted to explore the impact of missing data assumptions.. Longitudinal trends for FKSI-DRS scores did not differ by treatment arm. Taking nonignorable missing data into account, there were significant differences between treatment arms in the trend over time for physical functioning and global quality of life, with the everolimus arm exhibiting greater decreases. All three of these measures of health-related quality of life were significantly related to progression-free survival.. There was no evidence of a difference between everolimus and placebo in longitudinal patterns of disease-related symptoms, and little difference between the arms in physical functioning or global quality of life trends. This supports the conclusion that delay in tumor progression demonstrated by everolimus is associated with minimal impact on symptoms, physical functioning, or quality of life, as reported by patients.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Placebos; Protein-Tyrosine Kinases; Quality of Life; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Treatment Outcome

To date, no trial data exist comparing treatment outcomes for everolimus versus sorafenib. The current analysis indirectly compares the overall survival (OS) benefit of everolimus and sorafenib as second-line treatment options.. A single-arm sorafenib study is selected as a basis to match an everolimus sunitinib-refractory subpopulation of the RECORD-1 trial. Only patients with clear cell histology are included. An adjusted matching approach is taken where 1000 repeated random samples matched to the sorafenib population on risk score distribution are produced, and a 95% CI around the mean of all sampled median OS is generated.. The main outcome measures include adjusted median OS and progression-free survival.. In all, 45 clear cell histology sorafenib patients and 1000 samples of N=41 sunitinib-refractory everolimus patients are considered for analysis. After adjusted matching, the estimated median OS benefit is 32.0 [corrected] weeks (95% CI: 22, 64) and 81.5 weeks (95% CI:78, 86) for sorafenib and everolimus patients, respectively.. Results suggest that sunitinib-refractory metastatic renal cell carcinoma patients treated with everolimus may experience significantly improved OS outcomes compared to those treated with sorafenib. However, because this is not a randomized controlled trial, the results should be interpreted as those from an observational study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Disease-Free Survival; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Survival; Treatment Outcome

Safety and efficacy of two sirolimus (SRL)-based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher-than-expected biopsy-confirmed acute rejections (BCARs), was sponsor-terminated; therefore, Group 2 two-year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One- and 2-year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1- and 2-year modified intent-to-treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between-group malignancy rates were similar. The SRL-based regimens were not associated with improved outcomes for kidney transplantation patients.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus

Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.. We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.. 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).. Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.. Clinicaltrials.gov NCT00126672.

Topics: Adolescent; Adult; Aged; Angiomyolipoma; Anti-Bacterial Agents; Female; Humans; Kidney Neoplasms; Liver Neoplasms; Male; Middle Aged; Sirolimus; Tuberous Sclerosis; Vascular Endothelial Growth Factor D; Young Adult

Treatment of everolimus-resistant disease remains largely undefined in metastatic renal cell carcinoma (mRCC). We report on 40 patients (pts) who receive systemic treatment after failure of everolimus.. Forty pts received sunitinib (n=19), sorafenib (n=8), dovitinib (n=10) or bevacizumab/interferon (n=3) after failure of everolimus. Median progression-free survival (PFS), overall survival (OS) and best tumour response (according to Response Evaluation Criteria In Solid Tumors) were analysed retrospectively. Kaplan-Meier, log-rank test and Cox regression analyses were used to estimate or predict OS and PFS.. Treatment of everolimus-resistant disease was associated with a PFS of 5.5 months. (range 0.4-22.3) and an objective partial remission (PR) in 4 pts (10%) and stable disease (SD) in 22 pts (55%). In univariate analyses, first-line treatment with sorafenib was the only variable to correlate with a prolonged PFS of treatment in everolimus-resistant disease (P=0.036). However, its significance as a predictive marker for subsequent therapy could not be verified in multivariate analyses.. Vascular endothelial growth factor targeted therapy shows promising activity in everolimus-resistant metastatic renal cancer and warrants further studies.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Interferons; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyridines; Retrospective Studies; Sirolimus; Sorafenib; Treatment Failure; Treatment Outcome; Vascular Endothelial Growth Factor A

For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide.. This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels.. This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell carcinoma and increase the antitumor efficacy of everolimus.. ClinicalTrials.gov Identifier NCT01462214, EudraCT number 2010-024515-13, Netherlands Trial Register number NTR3085.

Topics: Administration, Oral; Antineoplastic Agents, Alkylating; Carcinoma, Renal Cell; Cyclophosphamide; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Netherlands; Sirolimus; Survival Analysis; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases

Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors.. To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus.. Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis.. Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%).. Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124).

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Pneumonia; Respiratory Function Tests; Severity of Illness Index; Sirolimus; Tomography, X-Ray Computed

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

To evaluate the efficacy and toxicity of the combination of bevacizumab, an angiogenesis inhibitor, and everolimus, an mTOR inhibitor, in the treatment of patients with advanced clear cell renal carcinoma.. Two groups of patients with metastatic renal cell carcinoma were eligible for this study: those with no previous treatment with targeted agents and those with previous treatment with sunitinib and/or sorafenib. All patients received bevacizumab 10 mg/kg intravenously every 2 weeks and everolimus 10 mg orally daily. Patients were evaluated for response after 8 weeks of treatment; patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred.. Eighty patients (50 untreated, 30 previously treated) entered this clinical trial. The combination of bevacizumab/everolimus showed activity in both groups. Median progression-free survivals in previously untreated and previously treated patients were 9.1 and 7.1 months, respectively. Overall response rates (30% and 23%) were similar in both groups. The regimen was well tolerated by most patients, with a toxicity profile as expected based on the known toxicities of these two agents. Grade 3 to 4 proteinuria was more frequent than expected (25%) and led to treatment discontinuation in six patients.. Bevacizumab/everolimus is active and well tolerated in the treatment of advanced clear cell renal cancer, either as first-line treatment or after treatment with sunitinib and/or sorafenib. The benefits of this combination regimen, versus sequential use of these two agents, requires further study.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Infusions, Intravenous; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome; United States

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

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

A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor-tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported.. Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression-free survival (PFS) and safety were assessed to the end of double-blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank-preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus.. The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio [HR], 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in ≥ 5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank-preserving structural failure time model, the survival corrected for crossover was 1.9-fold longer (95% confidence interval, 0.5-8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01).. These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Double-Blind Method; Everolimus; Humans; Kidney Neoplasms; Middle Aged; Neoplasm Metastasis; Placebos; Prognosis; Retreatment; 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

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

Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have been shown to have efficacy in renal cell cancer (RCC). This phase 2 study assessed the efficacy of daily oral dosing with everolimus in patients with RCC.. Patients had confirmed predominantly clear cell RCC; had received or=3 months was reported in 27 (73%) patients, and stable disease lasting >or=6 months was reported in 21 (57%) patients. Nausea (38% of patients), anorexia (38% of patients), diarrhea (31% of patients), stomatitis (31% of patients), pneumonitis (31% of patients), and rash (26% of patients) were common. Grade 3 of 4 adverse events included pneumonitis (18% of patients); transaminase elevations (10% of patients); thrombocytopenia, hyperglycemia, and alkaline phosphatase elevations (8% each of patients); and hyperlipidemia (5% of patients).. In the current study, everolimus demonstrated encouraging antitumor activity against metastatic RCC as indicated by a PFS >or= 6 months for approximately 70% of patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

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

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

Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy.. Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124.. All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity.. Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Double-Blind Method; Everolimus; Female; Humans; Immunosuppressive Agents; Karnofsky Performance Status; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Sirolimus

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

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

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

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

Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase gene USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients' primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X-depleted HeLa and renal cancer 786-O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients' sensitivity to mTOR inhibitors. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X-depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients, and represents a clinical strategy for increasing the sensitivity to these drugs.

Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Deubiquitinating Enzymes; Humans; Kidney Neoplasms; MTOR Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitin Thiolesterase

The mechanistic target of rapamycin (mTOR) kinase is a component of two signaling complexes that are known as mTOR complex 1 (mTORC1) and mTORC2. We sought to identify mTOR-phosphorylated proteins that are differently expressed in clinically resected clear cell renal cell carcinoma (ccRCC) relative to pair-matched normal renal tissue. Using a proteomic array, we found N-Myc Downstream Regulated 1 (NDRG1) showed the greatest increase (3.3-fold) in phosphorylation (on Thr346) in ccRCC. This was associated with an increase in total NDRG1. RICTOR is a required subunit in mTORC2, and its knockdown decreased total and phospho-NDRG1 (Thr346) but not NDRG1 mRNA. The dual mTORC1/2 inhibitor, Torin 2, significantly reduced (by ~100%) phospho-NDRG1 (Thr346). Rapamycin is a selective mTORC1 inhibitor that had no effect on the levels of total NDRG1 or phospho-NDRG1 (Thr346). The reduction in phospho-NDRG1 (Thr346) due to the inhibition of mTORC2 corresponded with a decrease in the percentage of live cells, which was correlated with an increase in apoptosis. Rapamycin had no effect on ccRCC cell viability. Collectively, these data show that mTORC2 mediates the phosphorylation of NDRG1 (Thr346) in ccRCC. We hypothesize that RICTOR and mTORC2-mediated phosphorylation of NDRG1 (Thr346) promotes the viability of ccRCC cells.

Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Phosphorylation; Proteomics; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

Declining kidney function in tuberous sclerosis complex (TSC) is often attributed to large lesions, including angiomyolipomas (AMLs) and cysts, that encroach on the normal parenchyma or that require intervention and loss of parenchyma from surgical debulking or embolization. Consequently, research on inhibitors of the mammalian target of rapamycin (mTOR), a protein complex implicated in TSC pathophysiology for its role in promoting cell growth and proliferation, has largely focused on their ability to reduce AML size. Clinical guidelines distilled from this research limit mTOR inhibition as a first-line treatment to patients with large AMLs. However, chronic kidney disease (CKD) occurs in patients without large AMLs or a history of renal intervention. Alternate mechanisms postulated for CKD in TSC may suggest a role for mTOR inhibition in this population. In this report, we present 2 cases of a microscopic variant of TSC kidney disease causing declining kidney function, as well as anecdotal evidence for the use of mTOR inhibition to improve kidney function in the absence of large AMLs. We highlight the importance of annual kidney function assessment in patients with TSC and suggest a low threshold for kidney biopsy in patients with declining glomerular filtration rate without a clear etiology clinically or radiographically.

Topics: Angiomyolipoma; Humans; Kidney; Kidney Neoplasms; Renal Insufficiency, Chronic; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Mammalian target of rapamycin (mTOR) inhibitors represent the standard of care for metastatic renal cell carcinoma (RCC). However, treatment outcomes are relatively poor, suggesting a potential problem with tolerating mTOR inhibitors. The aim of this study was to establish everolimus-resistant sublines and to compare their molecular characteristics with those of their counterparts.. Human-derived RCC, Caki-2, and 786-O cells were continuously exposed to everolimus at 1 μM, and the established resistant sublines were designated as Caki/EV and 786/EV, respectively. Cellular characteristics were compared between both cells.. Caki/EV and 786/EV cells showed a decrease in sensitivity to everolimus as well as other mTOR inhibitors. Expression of mTOR and its effectors exhibited no alteration in resistant sublines and their counterparts. However, phosphorylation of S6K, an index of mTOR activity, decreased in resistant sublines. PCR array analysis of mTOR signaling pathway-related factors indicated that the expression of INSR, TP53, and IGFBP3 increased in Caki/EV cells, whereas that of TELO2, HRAS, and SGK1 was up-regulated in 786/EV cells. The levels of DDIT4, DEPTOR, HIF1A, and PLD1 mRNAs decreased in both cell lines.. The novel everolimus-resistant Caki/EV and 786/EV cells exhibited cross-resistance to other mTOR inhibitors and decreased mTOR activity. Furthermore, down-regulation of DDIT4, DEPTOR, HIF1A, and PLD1 may contribute to everolimus resistance.

Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Everolimus; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; MTOR Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Forkhead Transcription Factors; Humans; Immunohistochemistry; Keratin-7; Kidney Neoplasms; Male; Middle Aged; Repressor Proteins; Sirolimus; TOR Serine-Threonine Kinases

Development of cancer, including renal cancer, is a major problem in immunosuppressed patients. The mTOR inhibitor Rapamycin (RAPA) is used as an immunosuppressive agent in patients with organ transplants and other immunological disorders; and it also has antitumorigenic potential. However, long-term use of RAPA causes reactivation of Akt, and ultimately leads to enhanced tumor growth. Honokiol (HNK) is a natural compound, which possesses both anti-inflammatory and antitumorigenic properties. In this study, we investigated the effect of a novel combination therapy using RAPA + HNK on allograft survival and post-transplantation renal tumor growth. We observed that it effectively modulated the expression of some key regulatory molecules (like Carabin, an endogenous Ras inhibitor; and Rubicon, a negative regulator of autophagy) that play important roles in tumor cell growth and survival. This combination induced toxic autophagy and apoptosis to promote cancer cell death; and was associated with a reduced expression of the tumor-promoting receptor tyrosine kinase AXL. Finally, we utilized a novel murine model to examine the effect of RAPA + HNK on post-transplantation renal tumor growth. The combination treatment prolonged the allograft survival and significantly inhibited post-transplantation tumor growth. It was associated with reduced tumor expression of Rubicon and the cytoprotective/antioxidant heme oxygenase-1 to overcome therapeutic resistance. It also downregulated the coinhibitory programmed death-1 ligand, which plays major role(s) in the immune escape of tumor cells. Together, this combination treatment has a great potential to restrict renal tumor growth in transplant recipients as well as other immunosuppressed patients.

Topics: Animals; Apoptosis; Autophagy; Biphenyl Compounds; Cell Line, Tumor; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Lignans; Mice; Organ Transplantation; Sirolimus; TOR Serine-Threonine Kinases

Renal cell carcinomas associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) are notoriously aggressive and represent the leading cause of death among patients with HLRCC. To date, a safe and effective standardized therapy for this tumor type is lacking. Here we show that the engineered synthetic therapeutic enzyme, Cyst(e)inase, when combined with rapamycin, can effectively induce ferroptosis in HLRCC cells in vivo. The drug combination promotes lipid peroxidation to a greater degree than cysteine deprivation or Cyst(e)inase treatment alone, while rapamycin treatment alone does not induce ferroptosis. Mechanistically, Cyst(e)inase induces ferroptosis by depleting the exogenous cysteine/cystine supply, while rapamycin reduces cellular ferritin level by promoting ferritins' destruction via ferritinophagy. Since both Cyst(e)inase and rapamycin are well tolerated clinically, the combination represents an opportunity to exploit ferroptosis induction as a cancer management strategy. Accordingly, using a xenograft mouse model, we showed that the combination treatment resulted in tumor growth suppression without any notable side effects. In contrast, both Cyst(e)inase only and rapamycin only treatment groups failed to induce a significant change when compared with the vehicle control group. Our results demonstrated the effectiveness of Cyst(e)inase-rapamycin combination in inducing ferroptotic cell death in vivo, supporting the potential translation of the combination therapy into clinical HLRCC management.

Topics: Animals; Carcinoma, Renal Cell; Cysteine; Cysts; Female; Ferroptosis; Humans; Kidney Neoplasms; Leiomyomatosis; Male; Mice; Neoplastic Syndromes, Hereditary; Sirolimus; Skin Neoplasms; Uterine Neoplasms

Mechanistic target of rapamycin (mTOR) inhibitors are macrocyclic lactone antibiotics derived from Streptomyces hygroscopicus that prevent T lymphocyte activation and B cell differentiation. Unlike calcineurin inhibitors (CNIs) that inhibit cytokine production, mTOR inhibitors block the cytokine signal transduction to arrest cells in the G1 to S phase. This class of drugs is commonly used for post-transplantation and cancer management because of its immunosuppressive and antiproliferative properties, respectively. The potential uses of mTOR inhibitors are heavily explored because of their impact on cell growth and proliferation. However, mTOR inhibitors have a broad range of effects that can result in adverse reactions, but side effects can occur with other immunosuppressive agents as well. Thus, the performance of mTOR inhibitors is compared to the outcomes and adverse effects of other immunosuppressive drugs or the combination of other immunosuppressants and mTOR inhibitors. Because mTOR regulates many downstream pathways, mTOR inhibitors can affect these pathways to manage various diseases. Sirolimus (rapamycin) is approved by the Food and Drug Administration (FDA) to treat post-renal transplantation and lymphangioleiomyomatosis (LAM). Everolimus is approved by the FDA to treat postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer in women, progressive neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma (AML) and tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC as well as renal and liver transplantation. Temsirolimus is approved by the FDA to treat advanced RCC. Opportunities to use mTOR inhibitors as therapy for other transplantation, metabolic disease, and cancer management are being researched. mTOR inhibitors are often called proliferation signal inhibitors (PSIs) because of their effects on proliferation pathways.

Topics: Angiomyolipoma; Carcinoma, Renal Cell; Cytokines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

We investigated patients with genitourinary cancer after kidney transplant and the effects of immunosuppression reduction and switching to mechanistic target of rapamycin inhibitors.. We retrospectively evaluated kidney transplant recipients seen at our center between January 2000 and January 2020. Patients with <1 year of follow-up were excluded.. Of 827 patients, genitourinary cancer was detected in 11 (1.3%): prostate cancer in 5 patients (45%), renal cell carcinoma in native kidney in 3 (27%), renal cell carcinoma in allograft kidney in 2 (18%), and transitional cell carcinoma of the bladder in 1 (9%). All patients had surgery. Two patients had bone metastasis due to prostate cancer at diagnosis. Two patients had allograft nephrectomy due to de novo renal cell carcinoma. Mean follow-up and age were 97 ± 45 months (range, 26-189) and 50 ± 10.2 years (19% female). After cancer diagnosis, excluding the 2 patients with allograft nephrectomy, immunosuppression was changed in 8 patients (88.8%) (1 patient received the same treatment before and after cancer diagnosis). Six patients received double-drug and 3 received triple-drug protocols. Of 9 patients, 2 were already using mechanistic target of rapamycin inhibitors before cancer diagnosis and 7 were switched: 4 to double-based and 3 to triple-based regimens. Six were switched from tacrolimus. With new treatments, patients showed no progressive kidney failure or rejection (38 ± 40 mo average follow-up). At last follow-up, mean glomerular filtration rate was 62.8 ± 34 mL/min/1.72 m2, which was similar to rate at cancer diagnosis (58.9 ± 24 mL/ min/1.72 m2; P = .78). During follow-up, no patients developed local recurrence of primary tumor or new metastasis, and none showed adverse effects after switch to mechanistic target of rapamycin inhibitors. Three patients died of malignancy-unrelated reasons (ileus, urinary sepsis, heart failure).. Mechanistic target of rapamycin inhibitor-based drugs can be an important maintenance immunosuppressive treatment option for kidney transplant recipients with genitourinary cancers.

Topics: Carcinoma, Renal Cell; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Male; Prostatic Neoplasms; Retrospective Studies; Sirolimus; Treatment Outcome; Urogenital Neoplasms

Facial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder impacting the mechanistic target of rapamycin (mTOR). Facial angiofibroma can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration causing psychological and social stress. To date, there is little or no evidence on the demographics, and other TSC features associated with facial angiofibroma or the use of mTOR inhibitor for the management of facial angiofibroma. This is a retrospective study of TSC Alliance's Natural History Database aimed to characterize facial angiofibroma and to evaluate features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors for the management of facial angiofibroma. Data in the NHD was obtained from 18 clinical sites in the US since 2006.. Of the 2240 patients, 2088 patients were enrolled in the US and data from 2057 patients were included in this analysis. The mean (median) age of overall TSC patients was 22.4 (19.0) years. A total of 69 patients were ≤ 5 years of age. Facial angiofibroma was noted in 1329 (64.6%) patients with TSC. Patients with facial angiofibroma were older on average (Mean: 25.9 [median, 23.0] vs. 16.0 [12.4 years] years, p < 0.0001). In patients with vs. without facial angiofibroma, TSC2 mutation (38.9% vs. 34.8%) was more common than TSC1 mutation (12.3% vs. 18.1%), and the incidence rate of most of the other TSC-related manifestations was significantly higher in patients with facial angiofibroma. Majority of patients had focal seizures (72.8% vs. 60.7%), followed by angiomyolipoma (63.7% vs. 21.8%) and renal cysts (59.4% vs. 33.5%). The age groups, 11-17 (odds ratio [OR], 2.53) and 18-45 years (5.98), TSC2 mutation (1.31), focal seizures (1.50), ADHD (1.47) angiomyolipoma (2.79), and renal cysts (2.63) were significantly associated with a higher risk of facial angiofibroma based on multivariate logistic regression. Abrasive or laser therapy was used by 17.1% and 2.6% patients, respectively. Topical mTOR inhibitor use was noted for 329 (24.8%) patients with facial angiofibroma. Overall systemic mTOR inhibitor use was observed in 399 (30.0%) patients for management of one or more TSC manifestations. Use of systemic mTOR inhibitor for facial angiofibroma was noted for 163 (12.3%) patients, among whom only 9 (0.7%) patients used exclusively for the management of facial angiofibroma. Of the patients with facial angiofibroma, 44.6% did not receive any treatment. Significantly higher use of topical mTOR inhibitor was associated with the 11-17 years age group (OR, 1.67), anxiety (1.57), angiomyolipoma (1.51), and renal cysts (1.33).. The presence of TSC2 mutations and most other TSC-related manifestations was significantly higher in patients with facial angiofibroma. About one-fourth of patients with facial angiofibroma used a topical mTOR inhibitor and use of systemic mTOR inhibitor for the management of facial angiofibroma or for the other manifestations was noted for 30.0%. About 44.6% of patients did not receive any treatment for the management of facial angiofibroma.

Topics: Adult; Angiomyolipoma; Humans; Immunosuppressive Agents; Kidney Diseases, Cystic; Kidney Neoplasms; MTOR Inhibitors; Retrospective Studies; Seizures; Sirolimus; Tuberous Sclerosis; United States; Young Adult

Metabolic characteristics of kidney cancers have mainly been obtained from the most frequent clear cell renal cell carcinoma (CCRCC) studies. Moreover, the bioenergetic perturbances that affect metabolic adaptation possibilities of papillary renal cell carcinoma (PRCC) have not yet been detailed. Therefore, our study aimed to analyze the in situ metabolic features of PRCC vs. CCRCC tissues and compared the metabolic characteristics of PRCC, CCRCC, and normal tubular epithelial cell lines. The protein and mRNA expressions of the molecular elements in mammalian target of rapamycin (mTOR) and additional metabolic pathways were analyzed in human PRCC cases compared to CCRCC. The metabolic protein expression pattern, metabolite content, mTOR, and metabolic inhibitor sensitivity of renal carcinoma cell lines were also studied and compared with tubular epithelial cells, as "normal" control. We observed higher protein expressions of the "alternative bioenergetic pathway" elements, in correlation with the possible higher glutamine and acetate consumption in PRCC cells instead of higher glycolytic and mTOR activity in CCRCCs. Increased expression of certain metabolic pathway markers correlates with the detected differences in metabolite ratios, as well. The lower lactate/pyruvate, lactate/malate, and higher pyruvate/citrate intracellular metabolite ratios in PRCC compared to CCRCC cell lines suggest that ACHN (PRCC) have lower Warburg glycolytic capacity, less pronounced pyruvate to lactate producing activity and shifted OXPHOS phenotype. However, both studied renal carcinoma cell lines showed higher mTOR activity than tubular epithelial cells cultured in vitro, the metabolite ratio, the enzyme expression profiles, and the higher mitochondrial content also suggest increased importance of mitochondrial functions, including mitochondrial OXPHOS in PRCCs. Additionally, PRCC cells showed significant mTOR inhibitor sensitivity and the used metabolic inhibitors increased the effect of rapamycin in combined treatments. Our study revealed in situ metabolic differences in mTOR and metabolic protein expression patterns of human PRCC and CCRCC tissues as well as in cell lines. These underline the importance in the development of specific new treatment strategies, new mTOR inhibitors, and other anti-metabolic drug combinations in PRCC therapy.

Topics: Carcinoma, Renal Cell; Citrates; Glutamine; Humans; Kidney Neoplasms; Lactates; Malates; MTOR Inhibitors; Pyruvates; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Autophagy; Biomarkers; Carcinogenesis; Carcinoma, Renal Cell; Cell Line, Tumor; Humans; Kidney Neoplasms; Mice; RNA Stability; RNA-Binding Proteins; RNA, Messenger; Sirolimus

Renal cell carcinoma (RCC) is the most common kidney malignancy and has a poor prognosis owing to its resistance to chemotherapy. Recently, microRNAs (miRNAs or miRs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer. In the present study, we aim to explore the potential role of miR-100 in RCC by targeting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) through the mammalian target of rapamycin (mTOR) pathway. Initially, microarray-based gene expression profiling of RCC was used to identify differentially expressed genes. Next, the expression of miR-100 and NOX4 was examined in RCC tissues and cell lines. Then, the interaction between miR-100 and NOX4 was identified using bioinformatics analysis and dual-luciferase reporter assay. Gain-of-function or loss-of-function approaches were adopted to manipulate miR-100 and NOX4 in order to explore the functional roles in RCC. The results revealed the presence of an upregulated NOX4 and a downregulated miR-100 in both RCC tissues and cell lines. NOX4 was verified as a target of miR-100 in cells. In addition, overexpression of miR-100 or NOX4 silencing could increase autophagy while decreasing the expression of mTOR pathway-related genes and migration and invasion. Conjointly, upregulated miR-100 can potentially increase the autophagy and inhibit the invasion and migration of RCC cells by targeting NOX4 and inactivating the mTOR pathway, which contributes to an extensive understanding of RCC and may provide novel therapeutic options for this disease.

Topics: Autophagy; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; MicroRNAs; NADPH Oxidase 4; Sirolimus; TOR Serine-Threonine Kinases

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

Renal cell carcinoma (RCC) is the most common type of kidney cancer, and accounts for approximately 3% of all malignancies. Metastatic RCC (mRCC) is not sensitive to traditional radiotherapy and chemotherapy, therefore targeted therapy has become an important treatment option. In this study, the second-line targeted drug everolimus (Afinitor), a mammalian target of rapamycin (mTOR) inhibitor, was investigated for its clinical efficacy and adverse events in mRCC after failure of first-line targeted therapy, such as sorafenib, sunitinib or pazopanib.. A total of 21 patients with mRCC who had been treated with surgery or other therapies such as tyrosine kinase inhibitors (TKIs) were given oral everolimus (10 mg/day) until disease progression. Clinical efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) 2 months after therapy, including complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The adverse events were observed, and timely treatment was provided.. Everolimus extended progression-free survival (PFS) in mRCC patients from 4 to 8 months (median 6.3 months). There were 3 patients with PR, 12 with SD, and 6 with PD, and the disease control rate (DCR) was 15/21 (71.4%). Common adverse events included stomatitis, rash, and pneumonitis.. This study provides further support that everolimus is still an important option in mRCC treatment after failure of first-line targeted therapy. However, clinical studies are still needed to further improve its therapeutic efficacy.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Sirolimus; Treatment Outcome

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

Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

Topics: Adult; Angiomyolipoma; Antibiotics, Antineoplastic; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Lipoma; Lymphangioleiomyomatosis; Male; Middle Aged; Prognosis; Retrospective Studies; Sirolimus; Tuberous Sclerosis; Young Adult

To evaluate the efficacy and safety of everolimus and sirolimus in patients with tuberous sclerosis complex-associated angiomyolipomas (TSC-AML).. We performed a multi-institutional retrospective study of TSC-AML patients treated with oral everolimus 10 mg or sirolimus 2 mg per day for at least 3 months. Angiomyolipoma volume was estimated using orthogonal measurements by MRI or CT. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events. All analyses were performed using SPSS 19.0 software.. Response rates were high in both groups. With the prolonged medication durations, the therapeutic efficacy of both agents became more significant. The TSC-AML volume reduction after 6 and 12 months was more pronounced in patients with everolimus than those with sirolimus. More than half of the patients treated with everolimus had ≥ 50% reduction, and approximately 80% of them had ≥ 30% reduction, which was higher than that in patients treated with sirolimus. Regarding safety, there was no significant difference in the incidence of AEs between the two groups.. Both everolimus and sirolimus are excellent therapeutic options for TSC-AML. However, everolimus has a better therapeutic efficacy than sirolimus, particularly in reducing TSC-AML volume. Everolimus is therefore recommended as the first choice of therapy for TSC-AML.

Topics: Angiomyolipoma; China; Everolimus; Humans; Kidney Neoplasms; Retrospective Studies; Sirolimus; Tuberous Sclerosis

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

Topics: Angiomyolipoma; Brain; Brain Neoplasms; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Magnetic Resonance Imaging; Multiple Pulmonary Nodules; Neoplasms, Multiple Primary; Rhabdomyoma; Sirolimus; Skin Neoplasms; Tomography, X-Ray Computed; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Young Adult

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

Patients with primary refractory metastatic renal cell carcinoma (mRCC) have a dismal prognosis and poor response to subsequent treatments. While there are several approved second-line therapies, it remains critical to choose the most effective treatment regimen.. We identified 7 patients with clear cell mRCC who had primary resistance to vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitor (ICI) combination therapy. The patients were treated with lenvatinib (a multitargeted TKI) plus everolimus (a mammalian target of rapamycin inhibitor). Among these 7 patients, 2 had prior TKI therapy, 3 had prior ICI therapy, and 2 had prior TKI and ICI therapy. We collected the patients' clinical characteristics, molecular profiles, treatment durations, and toxicity outcomes.. The median time to progression on prior therapies was 1.5 months. Lenvatinib plus everolimus was used either as a second-line (n = 4) or third-line (n = 3) therapy. As best responses, 3 patients had partial responses and 3 achieved stable disease. Patients were followed for ≥17 months; progression-free survival ranged from 3 to 15 months, and overall survival ranged from 4 to 17 months.. These 7 cases provide real-world data for the use of lenvatinib plus everolimus in patients with mRCC with primary resistance to first-line VEGF-targeted TKIs or ICI combination therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Everolimus; Female; Follow-Up Studies; Humans; Immunotherapy; Kidney Neoplasms; Male; Middle Aged; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Quinolines; Sirolimus; Survival Rate

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

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

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

miR-29b has been identified as a rapamycin-induced microRNA (miRNA) in Tsc2-deficient, mTORC1-hyperactive cells. The biological significance of this induction of miR-29b is unknown. We have found that miR-29b acts as an oncogenic miRNA in Tsc2-deficient cells: inhibition of miR-29b suppressed cell proliferation, anchorage-independent cell growth, cell migration, invasion, and the growth of Tsc2-deficient tumors in vivo. Importantly, the combination of miR-29b inhibition with rapamycin treatment further inhibited these tumor-associated cellular processes. To gain insight into the molecular mechanisms by which miR-29b promotes tumorigenesis, we used RNA sequencing to identify the tumor suppressor retinoid receptor beta (RARβ) as a target gene of miR-29b. We found that miR-29b directly targeted the 3'UTR of RARβ. Forced expression of RARβ reversed the effects of miR-29b overexpression in proliferation, migration, and invasion, indicating that it is a critical target. miR-29b expression correlated with low RARβ expression in renal clear cell carcinomas and bladder urothelial carcinomas, tumors associated with TSC gene mutations. We further identified growth family member 4 (ING4) as a novel interacting partner of RARβ. Overexpression of ING4 inhibited the migration and invasion of Tsc2-deficient cells while silencing of ING4 reversed the RARβ-mediated suppression of cell migration and invasion. Taken together, our findings reveal a novel miR-29b/RARβ/ING4 pathway that regulates tumorigenic properties of Tsc2-deficient cells, and that may serve as a potential therapeutic target for TSC, lymphangioleiomyomatosis (LAM), and other mTORC1-hyperactive tumors.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinoma, Renal Cell; Cell Movement; Cell Proliferation; Embryo, Mammalian; Female; Fibroblasts; Gene Expression Regulation; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; MicroRNAs; Receptors, Retinoic Acid; Sirolimus; Tuberous Sclerosis Complex 2 Protein; Tumor Cells, Cultured; Urinary Bladder Neoplasms; 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

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

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

The ever-changing tumor microenvironment constantly challenges individual cancer cells to balance supply and demand, presenting tumor vulnerabilities and therapeutic opportunities. Everolimus and temsirolimus are inhibitors of mTOR (mTORi) approved for treating metastatic renal cell carcinoma (mRCC). However, treatment outcome varies greatly among patients. Accordingly, administration of mTORi in mRCC is diminishing, which could potentially result in missing timely delivery of effective treatment for select patients. Here, we implemented a clinically applicable, integrated platform encompassing a single dose of [1-

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Humans; Image Processing, Computer-Assisted; Kidney Neoplasms; Magnetic Resonance Imaging; Mice; Pyruvic Acid; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

A 22-year-old manpresented as a refractory nephrotic syndrome with edema and proteinuria for more than one year. Physical examination revealed facial steatadenomas and periungual fibromas. Images were characterized by hamartomatous lesions in multiple organs, including the central nervous system, heart, lungs, liver, and kidneys. Gene tests verified TSC2 mutation and confirmed the diagnosis of tuberous sclerosis complex. The APOL1 mutation was positive in this patient, which indicated the possibility of steroid-resistant focal segmental glomerulonephritis. Thus, he was treated with sirolimus. Renal angiomyolipoma was shrunk, but proteinuria was not relieved (24h unine protein>10 g) and eventually led into renal insufficiency. Nondialytic therapy was initiated consequently. Losartan 50 mg/d was used to control proteinuria under the close watch of serum creatinine. A recent phone call on October 2018 failed to reachthe patient. Therefore, the follow-up information was not updated.. 患者男性，22岁。因水肿、蛋白尿1年余就诊，考虑为难治性肾病综合征。体检发现患者面部皮脂腺瘤、甲周纤维瘤，影像学显示中枢神经系统、心脏、肺、肝脏、肾脏等多系统受累，基因检查为TSC2基因突变，诊断结节性硬化症。基因检测同时发现APOL1基因突变，提示患者同时存在糖皮质激素抵抗型的局灶节段性肾小球硬化症的可能性。使用西罗莫司治疗，治疗初期肾脏血管平滑肌瘤体积缩小，但尿蛋白始终未缓解（24 h尿蛋白>10 g），最终仍发展为肾功能不全，开始非透析治疗，包括监测血压、血糖和血脂，餐中嚼服碳酸钙500 mg、3次/d，瑞舒伐他汀20 mg/d，补充维生素B(1)（10 mg/d）和叶酸（10 mg/d），使用氯沙坦50 mg/d控制尿蛋白并监测血肌酐变化。2018年10月电话随访未联系到患者，未能获得治疗近况。.

Topics: Angiomyolipoma; Apolipoprotein L1; Creatinine; Female; Glomerulonephritis, IGA; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Losartan; Male; Mutation; Nephrotic Syndrome; Proteinuria; Sirolimus; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Young Adult

To investigate factors influencing the volume response of everolimus and sirolimus in tuberous sclerosis complex (TSC) associated-angiomyolipomas (AML).. A retrospective analysis of 30 cases of TSC-AML treated by mTOR inhibitors (everolimus 18 cases, and sirolimus 12 cases) between April 2014 and November 2017 at our center was carried out. Epidemiological data, therapeutic response and influence factors were reviewed and analyzed. Age, sex, associated with SEGA and/or LAM or not, plasma rapamycin concentration, AML volume at baseline, and mean CT value of AML in the maximum cross-section at baseline were analyzed as potential influencing factors.. Eighteen patients with 32 lesions in everolimus group and 12 patients with 15 lesions in sirolimus group were included. There was no statistically significant difference of baseline characteristics except for involved side (P = 0.008) between two groups. The mean volume of AML was 1000 ± 1276 cm. Everolimus at 10 mg daily might be more effective than sirolimus at 2 mg daily in treatment of patients with TSC-AML. AML volume and mean CT value at baseline were factors influencing the short-term volume response of everolimus or sirolimus for TSC-AML.

Topics: Adult; Angiomyolipoma; Antibiotics, Antineoplastic; Everolimus; Female; Humans; Kidney Neoplasms; Male; Retrospective Studies; Sirolimus; Tomography, X-Ray Computed; Tuberous Sclerosis; Tumor Burden; Young Adult

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

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

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

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

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

Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined.. Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation.. NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs.

Topics: Adult; Angiomyolipoma; Antibiotics, Antineoplastic; Chemotherapy, Adjuvant; Hepatectomy; Humans; Kidney Neoplasms; Liver Neoplasms; Male; Mutation; Nephrectomy; Signal Transduction; Sirolimus; Spinal Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome; Tuberous Sclerosis Complex 2 Protein

Loss of Von Hippel-Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia-inducible factor (HIF-α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5-aminoimidazole-4-carboxamide-riboside (AICAR) as AMPK activator are used separately to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated. Treatment with drug combinations significantly decreased cell proliferation, increased cell apoptosis, and abolished Akt phosphorylation and HIF-2α expression in renal cell carcinoma cells, including primary cells isolated from kidney cancer patients. Significant decreases in cell migration and invasion were detected using drug combinations. Drug combinations effectively abolished binding of HIF-2α to the Akt promoter and effected formation of the DNA-protein complex in nuclear extracts from 786-O cells, as demonstrated using electromobility shift assay and examination of Akt promoter activity. Importantly, we tested the effect of each drug and the combined drugs on kidney tumor size in the nude mouse model. Our data show that treatment with rapamycin, AICAR, and rapamycin+AICAR decreased tumor size by 38%, 36%, and 80%, respectively, suggesting that drug combinations have an additive effect in reducing tumor size compared with use of each drug alone. Drug combinations effectively decreased cell proliferation, increased apoptotic cells, and significantly decreased p-Akt, HIF-2α, and vascular endothelial growth factor expression in tumor kidney tissues from mice. These results show for the first time that drug combinations are more effective than single drugs in reducing kidney tumor progression. This study provides important evidence that may lead to the initiation of pre-clinical trials in patients with kidney cancer.

Topics: Aminoimidazole Carboxamide; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Humans; Kidney Neoplasms; Male; Mice; Mice, Nude; Ribonucleotides; Sirolimus; Xenograft Model Antitumor Assays

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

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

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

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

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

Tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML) have a high lifetime risk of acute bleeding. MTOR-inhibitors are a promising novel treatment for TSC-AML, however adequate response to therapy can be difficult to assess. Early changes in MRI signal may serve as a novel early indicator for a satisfactory response to mTOR-inhibitor therapy of AML.. Thirty-eight patients with the definite diagnosis of tuberous sclerosis receiving everolimus therapy and n = 19 patients without specific therapy were included. 1.5 Tesla MRI was performed including sequences with a selective fat suppression. Patients were investigated prior to the initiation of therapy (baseline) and after <3 months (n = 21 patients), 3 to 6 months (n = 32) and 18 to 24 months (n = 28). Signal and size changes of renal AMLs were assessed at all different timepoints. Signal-to-noise-ratio (SNR), contrast-to-noise-ratio (CNR) and size of angiomyolipomas were evaluated.. Signal changes in 273 AMLs were evaluated. A significant and strong decrease of the CNR of AMLs following the initiation of therapy was measured in the fat-suppressed MR sequence at all time points, compared to the baseline: From 7.41±6.98 to 3.84±6.25 (p ≤ 0.05p = 0.002), 3.36±6.93 (p<0.0001), and 2.50±6.68 (p<0.0001) after less than 3 months, 3-6 months or 18-24 months of everolimus treatment, respectively. Also, a significant, however less pronounced, reduction of angiomyolipoma size in the different groups was measured (from baseline 2022.2±2657.7 mm2 to 1854.4±1670.9 mm2 (p = 0.009), 1875.5±3190.1 mm2 (p<0.001), and 1365.8 ± 1628.8 mm2 (p<0.0001) after less than 3 months, 3-6 months or 18-24 months of everolimus treatment, respectively). No significant changes in CNR (p>0.05) and size (p>0.05) were measured in the control group.. mTOR inhibitor therapy in TSC patients results in an early and pronounced fatty transformation of AMLs on MRI. Fatty transformation could represent a novel early indicator of response to therapy in this patient collective.

Topics: Adult; Angiomyolipoma; Female; Humans; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Signal-To-Noise Ratio; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

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

Topics: Aged; Antineoplastic Agents; Arm; Axitinib; Carcinoma, Renal Cell; Fat Necrosis; Humans; Kidney Neoplasms; Male; Sirolimus; Subcutaneous Fat

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

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

Neovascularisation supports the metastatic switch in many aggressive solid cancers. Tumour neovessels are mostly lined by endothelial cells sprouting from nearby capillaries, but they could also be contributed by circulating endothelial progenitor cells (EPCs). However, scant information is available about tumour-derived EPCs.. We carried out the first thorough, unbiased comparison of phenotype, function and genotype of normal versus tumour-derived endothelial colony forming cells (ECFCs), a truly endothelial EPC subtype. We used healthy donors-derived ECFCs (N-ECFCs) as control for breast cancer (BC)- and renal cell carcinoma (RCC)-derived ECFCs.. We found that both BC- and RCC-ECFCs belong to the endothelial lineage. Normal and tumour-derived ECFCs did not differ in terms of proliferative and tubulogenic rates. However, RCC-ECFCs were more resistant to rapamycin-induced apoptosis, whereas BC-ECFCs were more sensitive as compared with N-ECFCs. Gene expression profiling revealed 382 differentially expressed genes (DEGs; 192 upregulated and 150 downregulated) and 71 DEGs (33 upregulated, 38 downregulated) when comparing, respectively, BC- and RCC-ECFCs with N-ECFCs. Nonetheless, BC- and RCC-derived ECFCs shared 35 DEGs, 10 of which were validated by qRT-PCR; such 35 DEGs are organised in a gene network centred on FOS.. These results provide the first clear-cut evidence that BC- and RCC-derived ECFCs exhibit an altered gene expression profile as compared with N-ECFCs; yet, they share a common gene signature that could highlight novel and more specific targets to suppress tumour vascularisation.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Breast Carcinoma In Situ; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Renal Cell; Down-Regulation; Endothelial Progenitor Cells; Female; Gene Expression Regulation, Neoplastic; Genotype; Humans; Kidney Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Phenotype; Sirolimus; Transcriptome; Tumor Cells, Cultured; Up-Regulation

To use the tuberous sclerosis complex (TSC) Natural History Database to describe monitoring and treatment patterns among patients with TSC-related angiomyolipomas (AMLs).. This study used the TSC Natural History Database, which contains demographics, affected areas, diagnosis, and treatments for more than 1300 patients with TSC enrolled in 16 participating clinics during 2006-2013. Patient characteristics, AML monitoring tests, and AML treatments were assessed.. Among the 621 patients with TSC-related AMLs, 54% were female; 77% were Caucasian. Median age at TSC diagnosis was <1 year, whereas median age at AML diagnosis was 9.8 years. Most patients (84%) had at least 1 monitoring test following AML diagnosis. The most commonly used tests were magnetic resonance imaging (MRI; 65% of patients), ultrasound (62%), and computed tomography (41%). Between 2000 and 2012, MRI made up an increasingly large proportion of the total number of monitoring tests. Once diagnosed, 155 (25%) of patients received treatment for AML. The median time from diagnosis to first treatment was 3.8 years. The most common treatments were embolization (10%), everolimus (9%), sirolimus (6%), and nephrectomy (6%). The rate of nephrectomies declined over time, with none conducted during 2011 and 2012. No subsequent surgeries were reported among the 71 patients who received mTOR inhibitor as first-line therapy.. The use of MRIs increased between 2000 and 2012 among patients with TSC-AML. The majority of these patients did not receive treatment for AML. Use of nephrectomy decreased over the study period and was particularly rare in patients who received an mTOR inhibitor.

Topics: Adolescent; Angiomyolipoma; Databases, Factual; Embolization, Therapeutic; Everolimus; Female; Humans; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Nephrectomy; Protein Kinase Inhibitors; Sirolimus; Software; Treatment Outcome; Tuberous Sclerosis; Young Adult

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

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

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Sirolimus

Background Second targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin inhibitors (mTORis) and tyrosine kinase inhibitors (TKIs). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies. Methods Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI. Results Included patients (n = 325 for everolimus and n = 127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with <6 months on sunitinib or sorafenib as first TKI. No significant difference in PFS was observed in any subgroup. Limitations Important limitations include potential missing or inaccurate data in medical charts, and confounding due to unobserved factors. Conclusions In this retrospective chart review, no significant differences were detected in OS or PFS between axitinib and everolimus as second targeted therapy. Longer duration of first TKI was not associated with increased effectiveness of subsequent axitinib compared to everolimus.

Topics: Aged; Animals; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Comparative Effectiveness Research; Disease-Free Survival; Everolimus; Female; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Treatment Outcome; United States

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

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Sirolimus

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Sirolimus

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Sirolimus

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Sirolimus

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Pyridines; Sirolimus

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

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin 1 (mTORC1) signaling pathway is aberrantly activated in renal cell carcinoma (RCC). We previously demonstrated glycogen synthase kinase-3β (GSK-3β) positively regulated RCC proliferation. The aim of this study was to evaluate the role of GSK-3 in the PI3K/Akt/mTORC1 pathway and regulation of the downstream substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), ribosomal protein S6 kinase (S6K), and ribosomal protein S6 (S6RP).. We used human RCC cell lines (ACHN, Caki1, and A498) and, as normal controls, human renal proximal tubular epithelial cell (HRPTEpC) and non-tumorous kidney tissues that were obtained surgically for treatment of RCC patients. Rapamycin-resistant ACHN (ACHN/RR) cells were generated with chronic exposure of ACHN to rapamycin ranging from 1nM finally to 1 μM. Cell viability, cell cycling and direct interaction between GSK-3β and 4EBP1 were evaluated with MTS assay, flowcytometry and in vitro kinase assay with recombinant GSK-3β and 4EBP1products, respectively. Protein expression and phosphorylation of molecules associated with the PI3K/Akt/mTORC1 pathway were examined by immunoblotting. Effects of drug combination were determined as the combination index with CompuSyn software.. Overexpression and phosphorylation of 4EBP1 and S6RP together with GSK-3 activation were observed in RCC cell lines, but not in human normal kidney cells and tissues. Cell proliferation, p4EBP1 and pS6RP were strongly suppressed by GSK-3 inhibition. Rapamycin and LY294002 sufficiently decreased pS6RP, but only moderately p4EBP1. In vitro kinase assays showed that recombinant GSK-3β phosphorylated recombinant 4EBP1, and the effect was blocked by GSK-3 inhibitors. Different from rapamycin, AR- A014418 remarkably inhibited cell proliferation, and rapidly suppressed p4EBP1 and pS6RP in ACHN and ACHN/RR (in 30 min to 1 h). AR- A014418 and rapamycin combination showed additivity at lower concentrations, but antagonism at higher concentrations.. GSK-3β could directly phosphorylate 4EBP1 and activate the mTORC1 downstream signaling cascades to enhance protein biosynthesis and cell proliferation in RCC cell lines independent of rapamycin sensitivity. The direct GSK-3β/4EBP1 pathway might be an important subcellular mechanism as an inherent equipment for RCC cells to acquire clinical chemoresistance to mTORC1 inhibitors.

Topics: Adaptor Proteins, Signal Transducing; Carcinoma, Renal Cell; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromones; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Morpholines; Multiprotein Complexes; Phosphoproteins; Phosphorylation; Ribosomal Protein S6; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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

Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; DNA Damage; Female; Genome, Human; Humans; Kidney Neoplasms; Kinetics; Male; Mice; Mice, SCID; Molecular Dynamics Simulation; Mutation; Mutation, Missense; Plasmids; Protein Domains; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Von Hippel-Lindau Tumor Suppressor Protein

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

Lymphangioleiomyomatosis (LAM) and angiomyolipoma are two different, but related rare diseases. To the best of our knowledge, pulmonary LAM and pulmonary angiomyolipoma have not previously been observed in the same patient.. A 38-year-old woman presented with a dry cough and left flank pain. She had a right nephrectomy for renal angiomyolipoma 17 years ago. A magnetic resonance imaging scan demonstrated a round mass in the left kidney. A chest computed tomography scan demonstrated scattered small thin-walled cysts and multifocal round nodules in both lungs. A lung biopsy via video-assisted thoracoscopic surgery revealed that the cysts and nodules were manifestations of LAM and angiomyolipomas, respectively. After sirolimus therapy, the renal angiomyolipoma and metastasized pulmonary angiomyolipomas shrank, but pulmonary cysts were unchanged.. LAM and angiomyolipoma are significantly associated, and may coexist in the lungs in rare cases. Sirolimus is effective for both renal angiomyolipoma and metastasized pulmonary angiomyolipomas.

Topics: Adult; Angiomyolipoma; Female; Humans; Kidney Neoplasms; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Magnetic Resonance Imaging; Sirolimus; Thoracic Surgery, Video-Assisted; Tomography, X-Ray Computed

Rapamycin is a potential anti-cancer agent, which modulates the activity of mTOR, a key regulator of cell growth and proliferation. However, several types of cancer cells are resistant to the anti-proliferative effects of rapamycin. In this study, we report a MDM2/p53-mediated rapamycin resistance in human renal cancer cells.. Trypan blue exclusion tests were used to determine the cell viability. Changes in mRNA and protein expression were measured using real-time PCR and western blot, respectively. Xenograft models were established to evaluate the in vivo effects of rapamycin combined with a MDM2 inhibitor.. Rapamycin treatment suppresses the expression of MDM2 and exogenous overexpression of MDM2 in A498 cells contributes to rapamycin resistance. By establishing a rapamycin resistant cell line, we observed that MDM2 was significantly upregulated in rapamycin resistant cells than that in rapamycin sensitive cells. Importantly, the rapamycin resistant cells demonstrated attenuated accumulation of p53 in the nucleus in response to rapamycin treatment. Moreover, the inhibition of MDM2 by siMDM2 sensitizes A498 cells to rapamycin through the activation of p53. In both in vitro and in vivo models, the combination of rapamycin with the MDM2 inhibitor, MI-319, demonstrated a synergistic inhibitory effect on rapamycin resistant cells.. Our study reports a novel mechanism for rapamycin resistance in human renal cancer and provides a new perspective for the development of anti-cancer drugs.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Combinations; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Indoles; Injections, Subcutaneous; Kidney Neoplasms; Mice; Mice, Nude; Proto-Oncogene Proteins c-mdm2; RNA, Small Interfering; Signal Transduction; Sirolimus; Spiro Compounds; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Tuberous sclerosis (TSC) is an inherited syndrome in which tumours in multiple organs are characterised by activation of mammalian target of rapamycin complex 1 (mTORC1). Previous work suggests that mTORC1 activation is associated with feedback inhibition of Akt, a substrate of mTORC2. This could limit TSC-associated tumour growth but lead to paradoxical promotion of tumour cell survival upon treatment with mTOR inhibitors. However, Akt/mTOR signalling has not been fully investigated in TSC-associated tumours and it has been uncertain whether mTOR inhibition can prevent TSC-associated renal tumourigenesis. In this study, we investigated Akt/mTOR signalling in renal tumours using a Tsc2(+/-) mouse model and tested whether mTOR inhibition could prevent renal tumourigenesis. We found that all renal lesions including cysts, adenomas and carcinomas exhibited activation of both Akt and mTORC1 as evidenced by increased protein expression and phosphorylation of Akt and mTOR and their downstream targets. Protein kinase Cα was also highly expressed and phosphorylated in these lesions, consistent with activation of mTORC2. Surprisingly, IRS proteins were highly expressed, in contrast to a striking decrease seen in cultured Tsc2(-/-) mouse embryonic fibroblasts, suggesting one mechanism through which loss of feedback inhibition of Akt may occur in mTORC1 hyperactivated Tsc-associated tumours. Long-term treatment with rapamycin reduced both Akt and mTORC1 activity in normal kidney tissues and blocked the development of all types of renal lesions. In conclusion, in contrast to previous studies, we found that Akt signalling is not inhibited in Tsc-associated renal lesions and that by partially inhibiting the Akt/mTOR pathway, rapamycin is highly effective in preventing Tsc-associated tumours.

Topics: Animals; Antibiotics, Antineoplastic; Gene Expression Regulation, Neoplastic; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Mutant Strains; Multiprotein Complexes; Neoplasms, Experimental; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Nephrectomy; Pneumocystis carinii; Pneumonia, Pneumocystis; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases

This study, conducted in a 'field-practice' scenario, investigates the effectiveness and safety of everolimus in the second-line treatment of metastatic renal cell carcinoma (mRCC) patients.. mRCC patients, who started everolimus 10 mg/day after failure of first-line VEGF receptor-targeted tyrosine kinase inhibitor, were included in this study. Study end points were treatment response, progression-free survival and tolerability.. In total, 100 patients were assessed; the median duration of everolimus treatment was 7.1 months (95% CI: 5.7-8.5). A total of 19% of patients experienced a partial response and 62% of patients reached a stable disease. Median progression-free survival was 8 months (95% CI: 6.7-9.3). A total of 75% of patients experienced adverse events; no grade 4 adverse events were reported.. These findings, obtained in a 'field-practice' scenario, support the use of everolimus for mRCC patients who failed one VEGF receptor-targeted tyrosine kinase inhibitor.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; Sirolimus

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

Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus.. In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence.. Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis.. In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Differentiation; Drug Administration Schedule; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Mice; Mice, Nude; Neovascularization, Pathologic; Pyrroles; Sirolimus; Sunitinib; Xenograft Model Antitumor Assays

Mammalian targets of rapamycin inhibitors (mTOR inhibitors, mTORI) are indicated for the management of several cancer types, including hormone receptor--positive or HER2-negative breast cancer, advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, and tuberous sclerosis complex-related tumors. Among the most common adverse events of mTORI medication are discrete, large, solitary or multiple, superficial ulcers, almost exclusively situated on nonkeratinized oral mucosa, described as mTORI-associated stomatitis (mIAS). We describe the clinical presentation, course, and management of mIAS in three patients receiving the mTORI everolimus (Afinitor, Novartis, East Hanover, NJ). In two patients, mIAS manifested 9 and 30 days after first using everolimus, respectively, whereas in the third patient, it recurred 3 months after re-introduction of everolimus. Oral rinses with a "magic mouthwash" solution (dexamethasone oral drops solution 2 mg/mL × 10 mL, lidocaine gel 2% × 30 g, doxycycline suspension 50 mg/5 mL × 60 mL, and sucralfate oral suspension 1000 mg/5 mL × 150 mL, dissolved in sodium chloride 0.9% × 2000 mL) four times daily proved helpful in alleviating the symptoms, and the ulcers healed in 4 to 15 days. No side effects were recorded, and dose reduction or discontinuation of everolimus was not necessitated in two cases.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Sirolimus; Stomatitis

Sequential application of target drugs is standard procedure after renal cell carcinoma (RCC) patients develop resistance. To optimize the sequence, antitumour effects of the mTOR inhibitor RAD001 or the tyrosine kinase inhibitor (TKI) sorafenib on RCC cells with acquired resistance to the TKI sunitinib was evaluated. RCC cells were exposed to 1 μM sunitinib for 24 hrs (as control) and for 8 weeks (to induce resistance) and then switched to RAD001 (5 nM) or sorafenib (5 μM) for a further 8 weeks. Tumour cell growth, cell cycle progression, cell cycle regulating proteins and intracellular signalling were then investigated. Short-term application of sunitinib (24 hrs) induced cell growth blockade with accumulation in the G2/M phase. RCC cells became resistant to sunitinib after 8 weeks, demonstrated by accelerated cell growth along with enhanced cdk1, cdk2, loss of p27, activation of Akt, Rictor and Raptor. Switching to sorafenib only slightly reduced growth of the sunitinib resistant RCC cells and molecular analysis indicated distinct cross-resistance. In contrast, full response was achieved when the cancer cells were treated with RAD001. p19 and p27 strongly increased, phosphorylated Akt, Rictor and Raptor decreased and the tumour cells accumulated in G0/G1. It is concluded that an mTOR-inhibitor for second-line therapy could be the strategy of choice after first-line sunitinib failure.

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

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

Tuberous sclerosis complex (TSC) is an autosomal disease caused by inactivating mutations in either of the tumor suppressor genes TSC1 or TSC2. TSC-associated tumor growth is present in multiple tissues and organs including brain, kidney, liver, heart, lungs, and skin. In the kidney, TSC angiomyolipomas have aberrant vascular structures with abnormal endothelial cells, suggesting a role for endothelial mTORC1 function. In the current report, a genetically engineered mouse model (GEMM) with a conditional knockout allele of Tsc1 with a Darpp32-Cre allele displayed accelerated formation of both kidney cystadenomas and paw hemangiosarcomas. All mutant mice developed hemangiosarcomas on multiple paws by 6 weeks of age. By 16 weeks of age, the average mutant hind paw was 4.0 mm in diameter, nearly double the size of control mice. Furthermore, the hemangiosarcomas and kidney cystadenomas were responsive to intraperitoneal rapamycin treatment. Immunoblotting and immunostaining for phospho-S6 (pS6) and phospho-CAD showed that the effect of rapamycin on tumor size was through inhibition of the mTOR signaling pathway. Finally, elevated VEGF mRNA levels were also observed in hemangiosarcoma specimens. Because paw hemangiosarcomas are easily detectable and scorable for size and growth, this novel mouse model enables accelerated in vivo drug testing for therapies of TSC-related tumors.. These findings provide a strong rationale for simultaneous use of this conditional knockout mouse as an in vivo genetic model while seeking new cancer therapies for TSC-related tumors.

Topics: Animals; Antibiotics, Antineoplastic; Cystadenoma; Dopamine and cAMP-Regulated Phosphoprotein 32; Hemangiosarcoma; Injections, Intraperitoneal; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Neoplasms, Experimental; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Up-Regulation; Vascular Endothelial Growth Factor A

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

Ubenimex is a low-molecular-weight dipeptide with the ability to inhibit aminopeptidase N (APN) activity, enhance the function of immunocompetent cells and confer antitumor effects. We sought to characterize the effects of ubenimex on renal cell carcinoma (RCC). The 786-O and OS-RC-2 human RCC cell lines were positive for APN expression and ubenimex decreased APN activity without affecting the expression. Ubenimex suppressed the proliferation of both cell lines in a concentration‑dependent manner, as assessed by curve growth analysis and WST-8 proliferation assay. Wound healing and Matrigel invasion assays demonstrated that the migration and invasion of the RCC cells were also markedly suppressed by ubenimex. Furthermore, ubenimex increased the mortality of both RCC cell lines as determined by the LDH cytotoxicity assay. This affect was accompanied by increased levels of LC3B with no apparent effect on Caspase3; and we observed that autophagy increased significantly after ubenimex treatment in both RCC cell lines by electron microscopy. Moreover, rapamycin enhanced the cytotoxic effect of ubenimex, while 3-methyladenine reversed the effect, indicating that ubenimex cytotoxicity occured through an autophagy-related mechanism. To further assess the potential applicability of ubenimex in the treatment of RCC, we performed immunohistochemistry using tissue microarrays representing 76 RCC patients that underwent radical nephrectomy. The results showed that APN was expressed in most, but not all of the RCC tissues and that the expression was reduced in RCC as compared to the normal kidney tissues, suggesting a potential role for APN in RCC development. Collectively, these results indicated that ubenimex inhibits proliferation, migration and invasion of RCC cells. Ubenimex may induce autophagy, which may be associated with its effect on the growth arrest and the cell death of RCC cells.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Aminopeptidases; Antibiotics, Antineoplastic; Autophagy; Carcinoma, Renal Cell; Caspase 3; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Leucine; Middle Aged; Neoplasm Invasiveness; Sirolimus; Wound Healing; Young Adult

The aim of this study was to determine the effect of cancer-associated fibroblasts (CAFs) on renal cell carcinoma (RCC) tumor proliferation, migration, and development of drug resistance, thus underlying their potential as therapeutic targets in RCC patients. CAFs were grown in primary cultures. The in vitro model of interaction of RCC cell lines with CAFs was established. The influence of CAFs on the proliferation and migration ability as well as sensitivity to everolimus of RCC cells was further analyzed. Furthermore, Western blotting analysis was performed to examine the mechanisms mediating the effect of CAFs on RCC cells. The results of the MTT assay showed that coculture with CAFs increased the proliferation activity of both 786-O and Caki-1 cells compared with serum-free medium controls. The migration ability of RCC cell lines was also significantly enhanced after coculture treatment compared with untreated control. The inhibition effect of everolimus on 786-O and Caki-1 cells abrogated in cocultures with CAFs. The sensitivity of both two cell lines to everolimus was dramatically decreased when cocultured with CAFs. RCC cells cocultured with CAFs resulted in the activation of both proliferation-related (Erks) and survival-related (Akt) pathways. These data indicate that CAFs have an important role in supporting and promoting RCC. The interaction of CAFs with RCC cell lines stimulates tumor cell proliferation and migration and induces resistance to everolimus in RCC cells, suggesting that target of the tumor microenvironment may be a novel targeted therapies for RCC.

Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Everolimus; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Humans; Kidney Neoplasms; Proto-Oncogene Proteins c-akt; Sirolimus

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

Comparing prognostic factors for overall survival (OS) in community-practice metastatic renal cell carcinoma (mRCC) patients receiving second-line everolimus with those previously reported in clinical trials.. Two separate chart sets (2009 - 2012) were used to develop and validate a prognostic model for patients initiating second-line everolimus after first-line tyrosine kinase inhibitor (TKI).. Prognostic factors for OS have been identified and validated in separate samples.. One-year OS probabilities in the study (n = 220) and validation (n = 97) samples were 68 and 67%; median OS was 19 and 23 months - higher than the 1-year OS of 60% and median OS of 14.8 months of RECORD-1. Karnofsky performance score < 80%, duration of mRCC < 1 year, progression on first-line TKI, liver metastasis and clear cell histology were significant prognostic factors for shorter survival. One-year OS estimates were 84% for validation sample patients with 0 - 2 risk factors, 63% for 3 risk factors and 22% for 4 - 5 risk factors (log-rank p < 0.001).. Real-world prognostic factors for OS following second-line everolimus for mRCC were largely consistent with those previously identified in trial data; however, OS was longer in the practice setting than in clinical trials and was not associated with type of first-line TKI.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Prognosis; Protein Kinase Inhibitors; Sirolimus; United States

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

Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC.

Topics: Aged; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carcinoma, Renal Cell; Cell Transformation, Neoplastic; Coculture Techniques; Drug Resistance, Neoplasm; Female; Hepatitis A Virus Cellular Receptor 2; Heterografts; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Macrophages; Male; Membrane Proteins; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Proteins; Neoplasm Transplantation; Prognosis; Pyrroles; Sirolimus; Sunitinib; Tumor Cells, Cultured

Angiomyolipoma (AML) is a benign mesenchymal tumor composed of blood vessels, smooth muscle, and mature adipose tissue. AMLs in the kidney allografts are rare. We report a case of AML that was incidentally found 1 year after transplantation. Abdominal computed tomography showed a 4-cm renal tumor with contrast enhancement and an early washout pattern, resembling a renal cell carcinoma. Tumor biopsy proved a lipid-poor AML. Tumor diameter decreased to 2.4 cm after 6 months of treatment with sirolimus. Sirolimus not only reduces tumor size, but also benefits a transplant patient who needs immunosuppression.

Topics: Adult; Angiomyolipoma; Biopsy; Carcinoma, Renal Cell; Diagnosis, Differential; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Neoplasms; Kidney Transplantation; Nephrectomy; Renal Insufficiency; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome

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

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 study of kidney cancer pathogenesis and its treatment has been limited by the scarcity of genetically defined animal models. The FLCN gene that codes for the protein folliculin, mutated in Birt-Hogg-Dubé syndrome, presents a new target for mouse modeling of kidney cancer. Here we developed a kidney-specific knockout model by disrupting the mouse Flcn in the proximal tubules, thus avoiding homozygous embryonic lethality or neonatal mortality, and eliminating the requirement of loss of heterozygosity for tumorigenesis. This knockout develops renal cysts and early onset (6 months) of multiple histological subtypes of renal neoplasms featuring high tumor penetrance. Although the majority of the tumors were chromophobe renal cell carcinomas in affected mice under 1 year of age, papillary renal cell carcinomas predominated in the kidneys of older knockout mice. This renal neoplasia from cystic hyperplasia at 4 months to high-grade renal tumors by 16 months represented the progression of tumorigenesis. The mTOR and TGF-β signalings were upregulated in Flcn-deficient tumors, and these two activated pathways may synergetically cause renal tumorigenesis. Treatment of knockout mice with the mTOR inhibitor rapamycin for 10 months led to the suppression of tumor growth. Thus, our model recapitulates human Birt-Hogg-Dubé kidney tumorigenesis, provides a valuable tool for further study of Flcn-deficient renal tumorigenesis, and tests new drugs/approaches to their treatment.

Topics: Animals; Antibiotics, Antineoplastic; Carcinogenesis; Carcinoma, Renal Cell; Cysts; Disease Models, Animal; Hyperplasia; Kidney Neoplasms; Kidney Tubules, Proximal; Mice; Mice, Knockout; Proto-Oncogene Proteins; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transforming Growth Factor beta; Tumor Suppressor Proteins

Targeted therapy with sunitinib, pazopanib or everolimus has improved treatment outcome for patients with metastatic renal cell carcinoma patients (RCC). However, despite considerable efforts in sequential or combined modalities, durable remissions are rare. Immunotherapy like cytokine therapy with interleukin-2, T cell checkpoint blockade or adoptive T cell therapies can achieve long-term benefit and even cure. This raises the question of whether combining targeted therapy with immunotherapy could also be an effective treatment option for RCC patients. Sunitinib, one of the most frequently administered therapeutics in RCC patients has been implicated in impairing T cell activation and proliferation in vitro. In this work, we addressed whether this notion holds true for expansion of tumor-infiltrating lymphocytes (TILs) in sunitinib-treated patients. We compared resected primary RCC tumor material of patients pretreated with sunitinib with resection specimen from sunitinib-naïve patients. We found improved TIL expansion from sunitinib-pretreated tumor digests. These TIL products contained more PD-1 expressing TIL, while the regulatory T cell infiltration was not altered. The improved TIL expansion was associated with reduced intratumoral myeloid-derived suppressor cell (MDSC) content. Depletion of MDSCs from sunitinib-naïve RCC tissue-digest improved TIL expansion, proving the functional relevance of the MDSC alteration by sunitinib. Our in vivo results do not support previous in vitro observations of sunitinib inhibiting T cell function, but do provide a possible rationale for the combination of sunitinib with immunotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Everolimus; Female; Humans; Immunotherapy; Indazoles; Indoles; Interleukin-2; Kidney Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Molecular Targeted Therapy; Myeloid Cells; Neoplasm Metastasis; Programmed Cell Death 1 Receptor; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib; T-Lymphocytes; Treatment Outcome

Aberrations in the mTOR (mechanistic target of rapamycin) axis are frequently reported in cancer. Using publicly available tumor genome sequencing data, we identified several point mutations in MTOR and its upstream regulator RHEB (Ras homolog enriched in brain) in patients with clear cell renal cell carcinoma (ccRCC), the most common histology of kidney cancer. Interestingly, we found a prominent cluster of hyperactivating mutations in the FAT (FRAP-ATM-TTRAP) domain of mTOR in renal cell carcinoma that led to an increase in both mTORC1 and mTORC2 activities and led to an increased proliferation of cells. Several of the FAT domain mutants demonstrated a decreased binding of DEPTOR (DEP domain containing mTOR-interacting protein), while a subset of these mutations showed altered binding of the negative regulator PRAS40 (proline rich AKT substrate 40). We also identified a recurrent mutation in RHEB in ccRCC patients that leads to an increase in mTORC1 activity. In vitro characterization of this RHEB mutation revealed that this mutant showed considerable resistance to TSC2 (Tuberous Sclerosis 2) GAP (GTPase activating protein) activity, though its interaction with TSC2 remained unaltered. Mutations in the FAT domain of MTOR and in RHEB remained sensitive to rapamycin, though several of these mutations demonstrated residual mTOR kinase activity after treatment with rapamycin at clinically relevant doses. Overall, our data suggests that point mutations in the mTOR pathway may lead to downstream mTOR hyperactivation through multiple different mechanisms to confer a proliferative advantage to a tumor cell.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers, Tumor; Carcinoma, Renal Cell; Cell Proliferation; Databases, Genetic; DNA Mutational Analysis; Drug Resistance, Neoplasm; Genetic Predisposition to Disease; GTPase-Activating Proteins; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Monomeric GTP-Binding Proteins; Multiprotein Complexes; Neuropeptides; Phenotype; Point Mutation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Ras Homolog Enriched in Brain Protein; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transfection; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

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

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Pyridines; Sirolimus

Deficiency of tumor suppressor FLCN leads to the activation of the mTOR signaling pathway in human BHD-associated renal cell carcinomas (RCC). We have previously developed a renal distal tubule-collecting duct-Henle's loop-specific Flcn knockout (KO) mouse model (Flcnflox/flox/Ksp-Cre). This mouse model can only survive for three weeks after birth due to the development of polycystic kidney and uremia. Whether these cystic solid hyperplasia changes seen in those KO mice are tumorigenic or malignant is unknown. In this study, we demonstrated that genetic disruption of Flcn in mouse kidney distal tubule cells could lead to tumorigenic transformation of these cells to develop allograft tumors with an aggressive histologic phenotype. Consistent with previous reports, we showed that the mTOR pathway plays an important role in the growth of these Flcn-deficient allograft and human UOK 257-1 xenograft tumors. We further demonstrated that the mTOR inhibitor, sirolimus, suppresses the tumor's growth, suggesting that mTOR inhibitors might be effective in control of FLCN-deficient RCC, especially in BHD renal tumorigenesis.

Topics: Allografts; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Kidney Neoplasms; Mice, Knockout; Mice, Nude; Molecular Targeted Therapy; Phenotype; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Tumor Burden; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Pyridines; Sirolimus

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Pyridines; Sirolimus

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

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Sirolimus; Sorafenib

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

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Sirolimus

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

Circadian clock systems regulate many biologic functions, including cell division and hormone secretion in mammals. In this study, we explored the effects of circadian control on the pivot cell growth regulatory mTOR, the activity of which is deregulated in tumor cells compared with normal cells. Specifically, we investigated whether the antitumor effect of an mTOR inhibitor could be improved by changing its dosing schedule in RenCa tumor-bearing mice. Active, phosphorylated mTOR displayed a 24-hour rhythm, and levels of total mTOR protein (but not mRNA) also showed a circadian rhythm in RenCa tumor masses. Through investigations of the oscillation mechanism for mTOR expression, we identified the ubiquitination factor Fbxw7 as an mTOR regulator that oscillated in its expression in a manner opposite from mTOR. Fbxw7 transcription was regulated by the circadian regulator D-site-binding protein. Notably, administration of the mTOR inhibitor everolimus during periods of elevated mTOR improved survival in tumor-bearing mice. Our findings demonstrate that the circadian oscillation of mTOR activity is regulated by circadian clock systems, which influence the antitumor effect of mTOR inhibitors.

Topics: Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Circadian Rhythm; Everolimus; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Immunosuppressive Agents; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; NIH 3T3 Cells; Oscillometry; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Ubiquitin; Ubiquitin-Protein Ligases

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

Everolimus is an inhibitor of mammalian target of rapamycin, approved in patients with metastatic renal cell carcinoma. Besides, mammalian target of rapamycin inhibition has the ability to modulate T-lymphocyte homeostasis. Here, we report the case of a metastatic renal cell carcinoma patient treated with everolimus who presented unexpected prolonged tumor response. The monitoring of immune responses showed strong antitumor T-cell activation at the time of disease control, whereas a profound immunosuppression occurred when tumor progressed. Thus, a change of immune functions is associated with everolimus treatment. Our observation suggests that everolimus could shape immune responses, which in turn could contribute to its efficacy.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunologic Factors; Kidney Neoplasms; Lymphocyte Activation; Neoplasm Metastasis; Sirolimus; T-Lymphocyte Subsets; Treatment Outcome

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

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Indoles; Kidney Neoplasms; Male; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrroles; Sirolimus

Topics: Antineoplastic Agents; Cancer Vaccines; Carcinoma, Renal Cell; Humans; Immunotherapy; Kidney Neoplasms; Receptors, Vascular Endothelial Growth Factor; Sirolimus

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

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

The mTOR inhibitors have improved outcomes for patients with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for preselecting patients who are more likely to benefit from these agents. We undertook an exploratory translational study evaluating molecular cytogenetic changes in the context of outcomes from treatment with everolimus.. Ten patients with clear cell mRCC treated with everolimus were enrolled. Pretreatment tissue specimens were analyzed for molecular cytogenetic changes using fluorescence in situ hybridization and progression-free survival (PFS) data were obtained. Gene probes chosen for this analysis were: Von Hippel Lindau, fragile histidine triad, fibroblast growth factor receptor (FGFR) 1, FGFR3, PDGFβ, PDGFRβ, epidermal growth factor receptor, and myelocytomatosis viral oncogene.. Median PFS was 8.75 months. Two patients with the longest PFS (28 months and 23 months) had gain of PDGFβ and PDGFRβ. This was also observed in 3 other patients who had a PFS of 11.5 months, 8 months, and 5.5 months, respectively. Cytogenetic evolution was observed between primary and metastatic specimens.. PDGFβ and PDGFRβ gene status might be of relevance to everolimus therapy. Further research evaluating the utility of these potential biomarkers is required.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Renal Cell; Everolimus; Female; Follow-Up Studies; Humans; In Situ Hybridization, Fluorescence; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Pilot Projects; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor beta; Sirolimus

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Pneumonia; Sirolimus

Renal cell carcinoma (RCC) is the most common renal tumor and accounts for nearly 3 % of adult cancers. In the recent years, seven new targeted agents have been approved changing the treatment in metastatic RCC dramatically. So far, however, it remains unclear which sequence is best for those patients. This study analyzed retrospectively the outcome of patients treated with everolimus after failure of a vascular endothelial growth factor receptor-directed therapy and which therapies were used after everolimus.. In a retrospective analysis, patients receiving everolimus after failure of first-line VEGFR-directed therapy have been analyzed in regard to response, duration of treatment and subsequent therapies. In total, the data of 81 patients have been analyzed.. The most observed first-line therapy was sunitinib followed by sorafenib. Thirty-two patients received everolimus as second-line therapy, and 49 as third-line therapy. The median duration of treatment with everolimus was 4.5 months. Seventy-seven of eighty-one patients (95 %) received a further therapy after discontinuation of everolimus. The agents administered beyond were sunitinib (28.6 %), sorafenib (28.6 %) and 42.8 % received other therapies. Twenty-seven patients received an additional sequence of therapy (fourth to fifth line). Fifty-eight percentage of patients have still been alive at time of analysis.. The duration of everolimus therapy beyond failure of anti-VEGF-directed therapy and the reported time to progression was in the range of the RECORD-1 trial in daily practice as well. After failure of everolimus, reexposure to tyrosine kinase inhibitors is a common clinical practice and demonstrates a clinical benefit of therapies beyond everolimus.

Topics: Adult; Aged; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases

Limited data are available regarding patients with renal cell carcinoma and ESRD treated with TTs. The objective of this study was to explore the tolerability and safety of TT in patients with mRCC and ESRD.. We retrospectively identified patients with mRCC and ESRD treated at the University of Texas M.D. Anderson Cancer Center from 2002 to 2012. Patient characteristics including demographic, histology, treatment, and adverse events are reported. Duration of treatment (TOT) was determined from date of drug initiation to discontinuation. Overall survival (OS) was determined from initiation of TT to death. Statistics are descriptive.. Fourteen patients were identified. Ten patients had clear-cell histology and 4 had papillary histology. The median number of TTs per patient was 3 (range, 1-4) with median TOT of 28 months for all TTs. Eighty-eight percent of all toxicities were Grade 1 to 2; no Grade 4 toxicities were noted. Treatment discontinuations included 3 patients treated with sorafenib due to hand-foot syndrome, intolerable fatigue, and squamous cell skin cancer development; 2 patients treated with pazopanib due to intolerable fatigue and increased transaminase levels; and 1 patient treated with everolimus due to pneumonitis. Eight patients died from progressive disease. Median OS from initiation of TT was 28.5 months and 35 months from time of diagnosis.. Toxicities were mild to moderate and consistent with those reported in previous studies. TTs appear to be safe, well tolerated and produce antitumor response in patients with mRCC and ESRD receiving dialysis.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indazoles; Kidney Failure, Chronic; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Renal Dialysis; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Treatment Outcome

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

We report a case of the rechallenge of everolimus for metastatic renal cell carcinoma (RCC) after successful recovery from grade 3 interstitial lung disease (ILD). A 76-year-old man with metastatic RCC developed grade 3 ILD one month after the initiation of everolimus therapy (10 mg/day). ILD subsided in 4 months after the withdrawal of everolimus and treatment with corticosteroids. Half dose (5 mg/day) of everolimus was rechallenged for 9 months until another grade 3 ILD developed. Everolimus kept the disease under control for 13 months including the discontinuation period.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Enzyme Inhibitors; Everolimus; Fatal Outcome; Humans; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Prednisolone; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

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

The aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs).. A national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs.. Median progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013.. PFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Databases, Factual; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Drug Therapy; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Registries; Retrospective Studies; Sirolimus; Treatment Outcome

In clinical trials with no upper age limit, the proportion of older patients is usually small, probably reflecting the more conservative approach adopted by clinicians when treating the elderly. An exploratory analysis of elderly patients in the RECORD-1 Trial showed that patients ≥ 65 y.o. had superior median PFS than overall RECORD-1 population (5.4 months and 4.9 months, respectively). We investigated the efficacy, relative benefit and safety of Everolimus (EVE) as sequential therapy after failure of VEGFr-TKI therapy for older patients with metastatic renal cell cancer (mRCC), in daily practice.. 172 consecutive IRB approved patients with mRCC (median age 65, M:F 135/37, 78% clear cell) who received salvage EVE at 39 tertiary institutions between October 2009 and August 2011 were included in this analysis. Some 31% had progressed on sunitinib, 22% on sorafenib, 1% on axitinib, 41% on sequential therapy, and 5% had received other therapy. Patients with brain metastases were not included and 95% of the patients had a ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0 or 1. Previous radiotherapy was an exclusion criterion, but prior chemotherapy was permitted. Adequate organ function and hematologic parameters were mandatory. EVE administration was approved by the institutional review board at each participating institution and signed informed consent was obtained from all patients.. Median time of the whole cohort to last follow-up was 3.5 months (range 0.4-15.2 months). Forty four percent were continuing to take EVE at last follow- up. There were 86 (50%) patients ≥ 65 y.o. and 86 (50%) <65 y.o. The percentage of patients who showed PR/ SD was higher in the older group than in the younger one (5.9%/61.2% vs 1.2%/46.5%, respectively). Median survival of older patients was also significantly longer (3.5 +/- 0.31 vs 3.1 +/- 0.34, hazard ratio=0.45, CI; 0.255- 0.802). Analysis using Cox regression model adjusted for gender, PS, number of metastases, site of metastases, histology, smoking history and age detected an association between age and PFS (p=0.011). The frequency of adverse events in elderly patients treated with EVE was no greater than that in younger patients, although such toxicity may have had a greater impact on their quality of life.. Older patients should not generally be excluded from accepted therapies (mTOR inhibitors after failure of VEGFr-TKI therapy) for mRCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Retrospective Studies; Sirolimus; Treatment Outcome; Young Adult

Everolimus has demonstrated its efficacy in metastatic renal cell carcinoma (mRCC). Preliminary studies have shown high variability of everolimus blood concentrations (EBC). In other settings, its activity was correlated with EBC. We therefore decided to monitor EBC in patients treated with mRCC to assess its influence on oncologic outcomes.. Our study analyzed first 3 months' trough EBC levels in 42 patients treated in 4 French oncologic centers between March 2010 and August 2013. Patients presented a histologically confirmed diagnosis of mRCC and have failed prior anti-angiogenic (AA) therapies.. Median follow-up was 25.9 months. A total of 113 EBC were analyzed. The median trough concentration was 14.1 μg/L (range 2.6-91.5). Fourteen patients (67 %) versus 8 (38 %) patients with median EBC above or below 14.1 μg/L were free from progression at 6 months (p = 0.06). Median progression-free survival was 13.3 versus 3.9 months (HR 0.66 95 % CI 0.33-1.31; p = 0.23), and the median overall survival was 26.2 versus 9.9 months (HR 0.62 95 % CI 0.28-1.37; p = 0.24), for patients above or below the median value of trough concentrations, respectively.. Impact of drug exposure for AA tyrosine kinase inhibitors activity has been demonstrated in mRCC setting. Interpatients EBC variability was confirmed in the present study, and the results suggest a relationship between initial EBC within the first 3 months and the drug activity. It underlines the need to prospectively include EBC monitoring in future clinical trials to determine the need of its implementation in routine use.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Prognosis; Prospective Studies; Sirolimus; Treatment Outcome

Everolimus is positioned as second-line treatment for metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitors. We investigated retrospectively the efficacy and safety of everolimus in Japanese patients with advanced renal cell carcinoma in the clinical setting.. Nineteen patients who discontinued treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors because of disease progression or adverse events were administered everolimus. We evaluated progression-free survival, overall survival and tumor response rate of everolimus treatment. We also compared laboratory abnormalities and adverse events of everolimus treatment with those of prior vascular endothelial growth factor receptor-tyrosine kinase inhibitors therapy.. In all patients, median progression-free survival was 8.4 months and median overall survival was not reached at 25 months. The best objective response was complete response in 1 patient and stable disease in 15 patients. Eleven patients (58%) were intolerant and 8 (42%) were refractory to prior vascular endothelial growth factor receptor-tyrosine kinase inhibitors treatment. Median overall survival was significantly longer (P < 0.01) in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant (>25 months) than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects (4.3 months), and median progression-free survival tended to be better (P= 0.06) in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant (10.0 months) than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects (2.5 months). Two patients discontinued everolimus treatment because of adverse events.. In this study, the overall survival and progression-free survival were better in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects. The adverse event profiles of everolimus and vascular endothelial growth factor receptor-tyrosine kinase inhibitors were different. Patients intolerant to vascular endothelial growth factor receptor-tyrosine kinase inhibitors may tolerate everolimus well and have greater survival benefit from switching to everolimus than those refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitors.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Everolimus; Female; Humans; Japan; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Receptors, Vascular Endothelial Growth Factor; Retrospective Studies; Sirolimus; Survival Analysis; Treatment Outcome

Everolimus is indicated for the therapy of adults with advanced renal cell carcinoma after failure of treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). The aim of the study was a multicenter evaluation of efficiency and toxicity of everolimus in patients with metastatic renal carcinoma who received one line of VEGFR-TKI therapy. Data of one hundred and one patients were analyzed retrospectively. Patients received everolimus therapy between January 2010 and July 2013. Data were collected in 7 different oncology institutes in Hungary. Starting daily dose of everolimus was 10 mg in 28-day cycles. Physical and laboratory examinations were done monthly. Imaging tests were performed every 3 months. Tumor response and toxicity were evaluated according to RECIST 1.0 and NCI CTCAE 3.0, respectively. Statistical analysis was performed with SPPS version 20.0 for Windows. Currently 26 (27%) patients are being treated, 52 (54.1%) patients are alive. Median progression-free survival (PFS) was 5.7 months (95% CI 4.07-7.33). Partial remission, stable disease and progression occurred in 6 (6%), 71 (74%) and 19 (20%) patients, respectively. Median overall survival (OS) was 14.3 months (95% CI 6.99-19.81). PFS and OS results were more favorable in patients with ECOG 0-1. Survival was poorer in case of anemia, while better if PFS was longer than 12 months. In anemic patients with ECOG 0-1 and ECOG 2-3 OS was 30.9 and 7.7 months, respectively (p=0.031). Dose reduction and treatment delay happened in 8 (7.9%) and 12 (11.9%) cases, respectively. The most common side effects were the following: exanthema, edema, stomatitis, pneumonitis, anemia and abnormal kidney-, liver functions, blood sugar and cholesterol levels. According to the Hungarian experience, everolimus can safely be administered. PFS and OS results representing the centers' everyday practice, are similar to the results of the respective subgroups in the registration study.. Az everolimus elõrehaladott vesesejtes carcinoma kezelésére javallt, vascularis endothelialis növekedési faktor receptor (VEGFR) tirozinkináz-gátló (TKI) kezelést követõen. A vizsgálat célja metasztatikus veserákban szenvedõ betegeknél egy vonalban alkalmazott VEGFR-TKI kezelés utáni everolimusterápia hatékonyságának és toxicitási profiljának multicentrikus értékelése volt. 2010. 01.–2013. 07. között hazánk 7 onkológiai intézményében 101 betegnél indult everolimusterápia retrospektív elemzése. Az induló dózis 10 mg volt naponta, 28 napos ciklusokban. Fizikális és laborvizsgálat havonta, képalkotó kontroll 3 havonta történt. A tumorválaszt RECIST 1.0, a toxicitást NCI CTCAE 3.0 szerint értékeltük. Jelenleg 26 (27%) beteg kezelése zajlik, 52 beteg (54,1%) él. A medián progressziómentes túlélés (PFS) 5,7 hónap. Részleges remisszió 6 (6%), stabil betegség 71 (74%), progresszió 19 (20%). A medián teljes túlélés (OS) 14,3 hónap. A jobb általános állapotú (ECOG 0-1) betegek PFS és OS eredménye kedvezõbb volt. A túlélést csökkentette a fellépõ anémia (p=0,037), viszont javította a 12 hónapon túli PFS (p=0,001). A OS ECOG 0-1 és nem anémiás betegeknél 30,9, míg ECOG 2-3 és anémia esetén 7,7 hónap (p=0,031) volt. Dózisredukció 8 (7,9%), terápiahalasztás 12 (11,9%) esetben történt. Leggyakoribb mellékhatások: bõrkiütés, ödéma, stomatitis, pneumonitis, anémia, valamint vesefunkció-, májfunkció-, vércukor- és koleszterinszint-emelkedés. A hazai gyakorlatban szerzett tapasztalatok alapján az everolimus biztonsággal alkalmazható mTOR-gátló szer. A centrumok napi gyakorlata során elért PFS és OS hasonló a törzskönyvezõ vizsgálat megfelelõ alcsoportjainak eredményeihez.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Drug Eruptions; Edema; Everolimus; Female; Humans; Hungary; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Retrospective Studies; Sirolimus; Stomatitis; Treatment Failure; Treatment Outcome

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

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

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

The incidence of renal cell cancer (RCC) has been increasing for the past decade, and the 5-year survival for patients with metastatic RCC (mRCC) is rather low. Everolimus (RAD001), a new inhibitor for mammalian target of rapamycin (mTOR), is generally well tolerated, and demonstrates clinical benefit to patients with anti-VEGF-refractory mRCC. However, factors for selection of patients who may benefit from everolimus remain largely unknown. Here we aimed to explore potential molecular indicators for mRCC patients who may benefit from everolimus treatment.. Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients before everolimus treatment, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC (clinicaltrials.gov, NCT01152801), were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥ 6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules.. In these 18 patients, there were 1 PR, 15 SDs (including 9 SDs ≥ 6 months), and 2 progressive diseases (PD). The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR showed a better CBR (71.4% versus 0%, P = 0.023) and PFS time (11.3 versus 3.7 months, P = 0.001) than those patients with negative expression. The median PFS of patients with positive phospho-S6RP expression was longer (11.3 versus 3.7 months, P = 0.002) than that of patients negative for phospho-S6RP expression. However, expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus treatment with respect to CBR and PFS. Co-expression of phosphorylated mTOR, S6RP and/or 4EBP1 may improve the predictive value of the biomarkers for patients treated with everolimus.. The expression levels of phospho-mTOR and phospho-S6RP may be potential predictive biomarkers for efficacy of everolimus in patients with mRCC. Combining examinations of phosphorylated mTOR, S6RP and/or 4EBP1 may be a potential strategy to select mRCC patients sensitive to mTOR inhibitor treatment.

Topics: Adaptor Proteins, Signal Transducing; Adult; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Cell Cycle Proteins; China; Clinical Trials, Phase I as Topic; Disease-Free Survival; Everolimus; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Patient Selection; Phosphoproteins; Phosphorylation; Precision Medicine; Predictive Value of Tests; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Retrospective Studies; Ribosomal Proteins; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

Mammalian target of rapamycin inhibitor has exhibited promising anticancer activity for the treatment of renal cell carcinoma (RCC). However, many patients acquire resistance to therapeutic agents leading to treatment failure. The objective of this study was to determine whether treatment with YM155, a novel small molecule inhibitor of survivin, could reverse rapamycin resistance in a rapamycin-resistant RCC.. We induced a rapamycin-resistant clear cell carcinoma cell line (Caki-1-RapR). We showed that survivin gene expression was significantly up-regulated in Caki-1-RapR compared with that in its parent cells (Caki-1). Therefore, we hypothesized that targeting of survivin in Caki-1-RapR could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of rapamycin. We used both in vitro and in vivo models to test the efficacy of YM155 either as a single agent or in combination with rapamycin.. In Caki-1-RapR cells, YM155 significantly decreased survivin gene and protein expression levels and cell proliferation in a dose-dependent manner in vitro. In addition, YM155 treatment significantly reversed rapamycin resistance in cancer cells. In a nude mouse tumor xenograft model, YM155 significantly inhibited the growth of Caki-1-RapR tumor. In addition, YM155 significantly enhanced the antitumor effects of rapamycin in Caki-1-RapR tumor.. Our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of molecular target therapy in RCC.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Blotting, Western; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Kidney Neoplasms; Mice; Mice, Nude; Naphthoquinones; Real-Time Polymerase Chain Reaction; Sirolimus; Survivin; Up-Regulation; 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

Vascular endothelial growth factor (VEGF) inhibitors, including targeted therapy with tyrosine kinase inhibitors (TKIs) and the angiogenesis inhibitor bevacizumab, and mammalian target of rapamycin (mTOR) inhibitors are now the standard of care for metastatic renal cell carcinoma (mRCC). However, real-world treatment patterns are not well characterized.. To describe treatment patterns during the first, second, and third lines of targeted therapies for mRCC among community oncologists in the US.. Participating physicians recruited from a nationwide panel each identified up to 15 adult mRCC patients who initiated a second therapy after January 2010. Information extracted from medical records included types of targeted therapies, reasons for treatment choices, patterns of treatment discontinuation, and dose adjustments.. Thirty-six physicians contributed charts from 433 mRCC patients. Seventy-seven percent of patients received a VEGF inhibitor as first targeted therapy; 23% received an mTOR inhibitor. Among first-line VEGF users, second-line treatments were 66% mTOR and 34% VEGF inhibitors. Among first-line mTOR users, second-line treatments were 94% VEGF and 6% mTOR inhibitors. Sunitinib followed by everolimus was the most commonly used treatment sequence. Estimated median duration for second targeted therapy was 8.6 months, and median overall survival (OS) and progression-free survival (PFS) were 27.4 and 10.8 months, respectively. Efficacy, treatment guidelines and mechanism of action were the most important considerations for treatment choice.. LIMITATIONS include no adjustment for baseline characteristics, possible difference between physician-defined progression and central review in the clinical trial setting, and limited data availability for axitinib during the study period.. In this large retrospective chart review among community oncologists, VEGF-mTOR-VEGF was the most common treatment sequence for mRCC. The most common drugs were sunitinib in the first line and everolimus in the second line.

Topics: Adult; Animals; Antineoplastic Agents; Antineoplastic Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Medical Records; Middle Aged; Neoplasm Staging; Protein-Tyrosine Kinases; Pyrroles; Retrospective Studies; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome; Vascular Endothelial Growth Factor A

Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth.. We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC.. NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays.. Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.

Topics: Actin Cytoskeleton; Actins; Animals; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Synergism; Everolimus; Hedgehog Proteins; Humans; Indoles; Inhibitory Concentration 50; Kidney Neoplasms; Kruppel-Like Transcription Factors; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases; Neoplasm Micrometastasis; Nuclear Proteins; Paxillin; Proto-Oncogene Proteins c-akt; Pyridines; Pyrroles; Receptors, G-Protein-Coupled; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Smoothened Receptor; Sunitinib; Transcription Factors; Tumor Burden; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2

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

The development of de novo renal cell carcinoma (RCC) in a transplanted kidney is a rare condition. Currently, this is the second case report of a 41-year-old man in whom carcinoma of a renal allograft was detected by contrast-enhanced ultrasound (CEUS). An abdominal CT scan was not conclusive enough to differentiate between septal enhancement of a cyst and a low vascularized tumor. CEUS confirmed a solid, homogeneously enhancing but hypoechoic and hypovascular lesion compared to the surrounding kidney parenchyma without septal enhancement. Therefore, the patient underwent nephron-sparing surgery (NSS), affirming papillary RCC type 2. Graft function remained unchanged postoperatively; 12 months after NSS, no local recurrence or distant metastasis was described. CEUS seems to be a minimally invasive and efficient imaging option if other diagnostic tools cannot clearly exclude RCC, with the advantage of wide-ranging use, especially in cases of impaired renal function.

Topics: Adult; Carcinoma, Renal Cell; Contrast Media; Everolimus; Humans; Immunosuppressive Agents; Kidney; Kidney Neoplasms; Kidney Transplantation; Male; Neoplasm Metastasis; Nephrons; Postoperative Period; Recurrence; Renal Insufficiency; Sirolimus; Tacrolimus; Tomography, X-Ray Computed; Ultrasonography

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

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Everolimus; Evidence-Based Medicine; Humans; Kidney Neoplasms; Observational Studies as Topic; Randomized Controlled Trials as Topic; Sirolimus

Only few efforts have been taken to investigate the potential existence of disease-specific differences in the safety profile of everolimus. We analyze here the correlation between different patient and tumor characteristics on the safety profile of this molecule. Information on treatment response is also provided.. Consecutive patients with metastatic renal cell carcinoma (mRCC), pancreatic neuroendocrine tumors (pNET) or biliary tract cancer were included in this retrospective study. All patients received everolimus 10 mg/day or 5 mg/day. Clinical assessments were performed every 3 weeks.. In total, 98 patients were enrolled: 51 with mRCC, 25 with pNET and 22 with biliary tract cancer. The incidence of toxicities (any grade) was 76% with mRCC, 64% with pNET and 95% with biliary tract cancer. Patients with biliary tract cancer also presented a higher frequency of severe toxicities: 64 versus 18% with mRCC and 32% with pNET. Multivariate analysis disclosed that biliary tract cancer (odds ratio [OR]: 23.8; 95% CI: 6.0-117.8; p < 0.0001) is a predictive factor for the development of toxicities during everolimus treatment. No correlations between liver metastasis and toxicities were identified. Disease control rate (DCR) was 45% in mRCC patients, 96% in pNET and 50% for biliary tract cancer patients. pNET tumors were associated with a higher DCR than the mRCC and biliary tract cancer (OR vs mRCC: 66.7; 95% CI: 6.2-276.5; p = 0.004; OR vs biliary tract cancer: 2.6; 95% CI: 0.5-14.2; p = 0.025).. This study suggests that the safety profile of everolimus is acceptable in patients with either mRCC or pNET. In addition, the onset of toxicities is associated with an improved DCR. In patients with biliary tract cancer, everolimus is safe but associated with a higher incidence of adverse events.

Topics: Aged; Antineoplastic Agents; Biliary Tract Neoplasms; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Retrospective Studies; Sirolimus; Treatment Outcome

Angiomyolipomas (AMLs) are associated with cell fibrosis in kidney of Tuberous Sclerosis Complex patients. The mechanism by which the fibrotic proteins accumulated in AMLs has not been explored. In the present study, we investigated the role of Akt/tuberin/mTOR pathway in the regulation cell fibrosis proteins. AML cells that expressed low levels of tuberin showed less expression of N-cadherin and higher of vimentin proteins compared to HEK293 cells. AML cells infected with Ad-tuberin showed a significant decrease in vimentin and an increase in N-cadherin protein expression. In addition, cells treated with rapamycin showed a significant increase in p-Akt and a decrease in p-p70S6K that was associated with a decrease expression of vimentin and a slight increase expression in N-cadherin. On the other hand, cells treated with Akt inhibitor revealed a significant decrease in p-Akt and p-p70S6K that was associated with a significant decrease in vimentin and an increase in N-cadherin expression. In addition, cells transfected with DN-Akt or DN-S6K show significant increase expression in N-cadherin and a decrease in vimentin. Moreover, cells transfected with siRNA against rictor or siRNA against raptor resulted in a decrease in vimentin and an increase N-cadherin expression. Kidney tumors from TSC patients showed significant decrease in N-cadherin and significant increased in vimentin protein expression compared to control kidney tissues. These data comprise the first report to provide the role of Akt/tuberin/mTORC1/2 in the regulation of N-cadherin and vimentin that are involved in the progression of fibrosis in kidney tumor of TSC patients.

Topics: Angiomyolipoma; Antigens, CD; Cadherins; Down-Regulation; HEK293 Cells; Humans; Kidney Neoplasms; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Up-Regulation; Vimentin

Renal angiomyolipomas (AMLs) are frequent in tuberous sclerosis and are responsible for a significant proportion of the morbidity in adulthood, mainly from bleeding complications, which are correlated to the size of the AMLs. We describe the case of a 19-year-old female with multiple bilateral renal angiomyolipomas.. The renal AMLs measured up to 6 cm in size. She was first treated with a low dose of the mammalian target of rapamycin (mTOR) inhibitor sirolimus (up to 3 mg/day over a 12-month period) and following significant AML size reduction, percutaneous cryoablation was performed. No side-effects of either treatment were reported. At 12 months post-cryoablation, no recurrence of the AML was noted.. This is the first report of this treatment strategy and the case study reveals that combining a low dose of an mTOR inhibitor with percutaneous cryoablation to treat small tumors mitigates the side-effects while providing a good clinical outcome. This therapeutic approach is a novel tool for the clinician involved in the management of patients with tuberous sclerosis.

Topics: Adult; Angiomyolipoma; Cryosurgery; Female; Humans; Kidney Neoplasms; Neoadjuvant Therapy; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tuberous Sclerosis; Young Adult

The aim of the present study was to evaluate how treatment with everolimus changes readouts of the pulmonary function test (PFT) in patients with metastatic renal cell carcinoma (mRCC). We also attempted to determine whether changes of PFT or everolimus-associated non-infectious pneumonitis (NIP) might affect the efficacy of everolimus.. The results of PFTs, radiological reports and medical records of 36 mRCC patients treated with everolimus after failure to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) were reviewed.. Whereas 9 patients (30%) developed radiological changes consistent with everolimus-associated NIP (pneumonitis group), 27 were included in the non-pneumonitis group. The baseline value of the diffusing capacity for carbon monoxide divided by the alveolar volume (DLco/VA) was 90%. It decreased significantly as the duration of treatment increased (p<0.01). There was no significant difference in DLco/VA values between patients with and without NIP either at baseline (p=0.28) and 6 weeks after the initiation of everolimus therapy (p=0.18). The changes in DLco/VA between baseline and 6 weeks did not differ between the two groups (p=0.55). Time-dependent covariate Cox analysis, indicated that the decrease in DLco/VA was not correlated with the efficacy of everolimus in terms of progression-free survival (PFS; HR=1.0, p=0.94) and overall survival (OS; HR=0.98, p=0.18), whereas development of NIP was associated with worse PFS (HR=4.60, p=0.01).. Patients with mRCC who are receiving everolimus therapy display a reduction in DLco/VA over time. However, neither the baseline DLco/VA nor the change in DLco/VA over time can help predict either development of NIP or the efficacy of everolimus.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carbon Monoxide; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pneumonia; Pulmonary Diffusing Capacity; Respiratory Function Tests; Sirolimus; Treatment Outcome

Topics: Australia; Carcinoma, Renal Cell; Everolimus; Humans; Immunosuppressive Agents; Insurance, Health, Reimbursement; Kidney Neoplasms; Sirolimus

Everolimus was recently introduced as a second-line treatment for renal cell carcinoma (RCC) and many other cancers. Several prospective studies have shown that serum creatinine levels are increased in a significant proportion of patients receiving everolimus. However, data on the occurrence of acute kidney injury (AKI) during everolimus treatment in clinical practice are sparse. Here, we report the incidence, risk factors, and clinical significance of AKI associated with everolimus treatment in patients with cancer.. We analyzed patients who received everolimus for more than 4 weeks as an anticancer therapy. AKI was defined as increase in creatinine levels from baseline levels greater than 1.5-fold.. The majority of the 110 patients enrolled in this analysis had RCC (N=93, 84.5%). AKI developed in 21 (23%) RCC patients; none of the patients (N=17) with other cancers had AKI. Fourteen of 21 cases were considered to be everolimus-associated AKI, in which there were no other nephrotoxic insults other than everolimus at the onset of AKI. The incidence of AKI increased progressively as baseline estimated glomerular filtration rate (eGFR) decreased (10% in subjects with eGFR >90 mL/min/1.73 m2, 17% in subjects with eGFR 60-90 mL/min/1.73 m2, 28% in subjects with eGFR 30-60 mL/min/1.73 m2, and 100% in subjects with eGFR 15-30 mL/min/1.73 m2; P=0.029 for trend). Baseline eGFR was an independent risk factor for the development of everolimus-associated AKI (hazard ratio per 10 mL/min/1.73 m2 increase, 0.70; 95% confidential interval, 049-1.00; P=0.047). Nine of 14 patients with everolimus-associated AKI continued receiving the drug at a reduced dose or after a short-term off period. Administration of the drug was discontinued in four of 14 patients because of progression of an underlying malignancy. Only one patient stopped taking the drug because of AKI.. This paper suggests that AKI is a common adverse effect of everolimus treatment, especially in subjects with impaired renal function. However, the occurrence of AKI did not require the discontinuation of the drug, and the treatment decision should be made via a multidisciplinary approach, including the assessment of the oncological benefits of everolimus and other therapeutic options.

Topics: Acute Kidney Injury; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Creatinine; Everolimus; Female; Glomerular Filtration Rate; Humans; Incidence; Kidney Neoplasms; Male; Middle Aged; Risk Factors; Sirolimus

To evaluate the impact of sequential targeted therapy including vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) and everolimus on progression-free survival (PFS) in metastatic renal carcinoma.. A total of 17 patients of metastatic renal cell carcinoma from Department of Kidney Cancer and Melanoma, Peking University Cancer Hospital since January 2008 until April 2014 were enrolled into this retrospective study. They took at least 2 lines of VEGFR-TKIs and everolimus. The data of total PFS and PFS of each therapy were extracted and analyzed.. The sequential targeted therapies affected total PFS (18.0 vs 46.0 months, Kaplan-Meier survival analysis, P = 0.015) with a statistical dislike of VEGFR-TKI/VEGFR-TKI/mTOR inhibitor (TTM) over VEGFR-TKI/mTOR inhibitor/VEGFR-TKI (TMT) , HR = 5.44 (Cox regression analysis, 95% CI 1.18-25.06).. TMT may prolong the total PFS of metastatic renal cell carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Protein Kinase Inhibitors; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Vascular Endothelial Growth Factor A

To observe the effects of normal human renal fibroblast (NHRF) on renal cell carcinoma cell lines.. Renal cell carcinoma (RCC) cell lines 786-O and Caki-1 were co-cultured with NHRF for assessing the proliferation and migratory capacities of renal cell carcinoma cell lines and the sensitivity to everolimus.. Co-culturing with NHRF substantially increased the proliferation capacity of both RCC cell lines (786-O: 2.35 ± 0.05 vs1.93 ± 0.15, P = 0.01;Caki-1: 2.35 ± 0.21 vs 1.24 ± 0.11, P = 0.001). Similarly the migratory capacities of both cell lines became significantly enhanced after co-culturing (786-O: 1.53 ± 0.11 vs 0.98 ± 0.11, P = 0.04; Caki-1: 1.53 ± 0.11vs 0.98 ± 0.11, P = 0.04) compared with untreated control. Furthermore, the sensitivities of both cell lines to everolimus (1, 5, 10 µmol/L) dramatically decreased in those pre-co-cultured with NHRF (786-O:P value 0.04, 0.35, 0.18); Caki-1: P value 0.02, 0.03, 0.024).. NHRF promotes the proliferation and migration capacities of 786-O and Caki-1. And it may be involved in the resistance of RCC to everolimus.

Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Everolimus; Fibroblasts; Humans; Kidney; Kidney Neoplasms; Sirolimus

A 76-year-old female with advanced renal cell carcinoma had been treated with everolimus for 3 months. She visited our hospital because of a cough and fever lasting a few days. Chest X-rays showed bilateral infiltrative shadows, and a chest computed tomography scan showed homogeneous ground-glass opacities with mosaic patterns, especially in the apical region. The laboratory results revealed a decreased white blood cell count with lymphocytopenia and high levels of lactate dehydrogenase, C-reactive protein and KL-6. Pneumonitis was suspected and, therefore, everolimus therapy was interrupted. At that time, the pneumonitis was thought to be drug-induced interstitial lung disease. However, it was not possible to rule out pneumocystis pneumonia, because the patient was immunocompromised and the computed tomography findings suggested the possibility of pneumocystis pneumonia. The pneumonitis progressed rapidly and the patient developed respiratory failure, so we performed bronchoalveolar lavage to make a definitive diagnosis, and simultaneously started treatment with prednisolone and trimethoprim-sulfamethoxazole to cover both interstitial lung disease and pneumocystis pneumonia. A polymerase chain reaction assay of the bronchoalveolar lavage fluid was positive for Pneumocystis carinii DNA, and the serum level of β-d-glucan was significantly elevated. Thus, the patient was diagnosed with pneumocystis pneumonia, which was cured by the treatment. Interstitial lung disease is a major adverse drug reaction associated with everolimus, and interstitial lung disease is the first condition suspected when a patient presents with pneumonitis during everolimus therapy. Pneumocystis pneumonia associated with everolimus therapy is rare, but our experience suggests that pneumocystis pneumonia should be considered as a differential diagnosis when pneumonitis is encountered in patients receiving everolimus therapy.

Topics: Aged; Anti-Infective Agents; Antineoplastic Agents; Bronchoalveolar Lavage; Carcinoma, Renal Cell; Diagnosis, Differential; Drug Administration Schedule; Everolimus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Neoplasms; Lung Diseases, Interstitial; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Respiratory Insufficiency; Sirolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

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

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

The importance of neovascularization for primary and metastatic tumor growth fostered numerous clinical trials of angiogenesis inhibitors either alone or in combination with conventional antineoplastic therapies. One challenge with the use of molecularly targeted agents has been the disconnection between size reduction and tumor biologic behavior, either when the drug is efficacious or when tumor resistance emerges. Here, we report the synthesis and characterization of (64)Cu-NOTA-bevacizumab as a PET imaging agent for imaging intratumoral VEGF content in vivo. (64)Cu-NOTA-bevacizumab avidly accumulated in 786-O renal carcinoma xenografts with lower levels in host organs. RAD001 (everolimus) markedly attenuated (64)Cu-NOTA-bevacizumab accumulation within 786-O renal carcinoma xenografts. Tumor tissue and cellular molecular analysis validated PET imaging, demonstrating decreases in total and secreted VEGF content and VEGFR2 activation. Notably, (64)Cu-NOTA-bevacizumab PET imaging was concordant with the growth arrest of RAD001 tumors. These data suggest that immunoPET targeting of angiogenic factors such as VEGF could be a new class of surrogate markers complementing the RECIST criteria in patients receiving molecularly targeted therapies.

Topics: Animals; Antibodies, Monoclonal, Humanized; Bevacizumab; Cell Line, Tumor; Cell Transformation, Neoplastic; Copper Radioisotopes; Everolimus; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Humans; Immunoconjugates; Kidney Neoplasms; Mice; Neovascularization, Pathologic; Phosphorylation; Positron-Emission Tomography; Sirolimus; Treatment Outcome; Vascular Endothelial Growth Factor A

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

Topics: Antineoplastic Agents; Biomarkers, Pharmacological; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; L-Lactate Dehydrogenase; Male; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors.. We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau (VHL) gene status, both in vitro and in nude mice. We studied their direct antiangiogenic effects on human umbilical vein endothelial cells.. Both IMO and everolimus inhibited in vitro growth and survival of RCC cell lines, and their combination produced a synergistic inhibitory effect. Moreover, everolimus plus IMO interfered with EGFR-dependent signaling and reduced VEGF secretion in both VHL wild-type and mutant cells. In RCC tumour xenografts, IMO plus everolimus caused a potent and long-lasting cooperative antitumour activity, with reduction of tumour growth, prolongation of mice survival and inhibition of signal transduction. Furthermore, IMO and everolimus impaired the main endothelial cell functions.. A combined treatment with everolimus and IMO is effective in VHL wild-type and mutant models of RCC by interfering with tumour growth and angiogenesis, thus representing a potentially effective, rationale-based combination to be translated in the clinical setting.

Topics: Animals; Carcinoma, Renal Cell; Cell Growth Processes; Cell Line, Tumor; Drug Synergism; Everolimus; Human Umbilical Vein Endothelial Cells; Humans; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Oligonucleotides; Random Allocation; Sirolimus; Toll-Like Receptor 9; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays

We retrospectively analyzed metastatic renal cell carcinoma (RCC) patients treated with 3 targeted agents. Patients started the sequence with a tyrosine kinase inhibitor (TKI), sunitinib or sorafenib, and were divided into 2 groups based on the order in which they received the other reciprocal TKI and everolimus (EVE): TKI-TKI-EVE group (n = 19) and TKI-EVE-TKI group (n = 14). Median progression-free survival (PFS) with first TKI was 13 months in the TKI-TKI-EVE group and 10 months in the TKI-EVE-TKI group. PFS with the second agent showed a trend in favor of the TKI-TKI-EVE sequence, with a median of 11 versus 6.5 months, whereas median PFS with the third agent was 6 months in both groups. Total PFS also showed a trend in favor of the TKI-TKI-EVE sequence with a median of 31 versus 23 months. Median overall survival (OS) was 38 months in both groups, with more patients receiving subsequent treatment in the TKI-EVE-TKI group. The subgroup of patients no long-term responders (≤9 months) to first TKI showed similar outcomes irrespective of the sequence. The subgroup of long-term responders to first TKI (>9 months) who received the other TKI instead of EVE had better outcomes in terms of median PFS with the second agent (13 vs. 5.5 months; p = 0.0271), median total PFS (39.5 vs. 23.5 months; p = 0.0415), and median OS (46 vs. 38 months). In conclusion, no apparent advantage was observed with early use of EVE in advanced RCC, even in those patients who did not benefit long from first-line TKI, whereas long-term duration of first-line TKI seems to be predictor of second-line TKI efficacy.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib

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

Deficiency in tuberin results in activation the mTOR pathway and leads to accumulation of cell matrix proteins. The mechanisms by which tuberin regulates fibrosis in kidney angiomyolipomas (AMLs) of tuberous sclerosis patients are not fully known.. In the present study, we investigated the potential role of tuberin/mTOR pathway in the regulation of cell fibrosis in AML cells and kidney tumor tissue from tuberous sclerosis complex (TSC) patients.. AML cells treated with rapamycin shows a significant decrease in mRNA and protein expression as well as in promoter transcriptional activity of alpha-smooth muscle actin (α-SMA) compared to untreated cells. In addition, cells treated with rapamycin significantly decreased the protein expression of the transcription factor YY1. Rapamycin treatment also results in the redistribution of YY1 from the nucleus to cytoplasm in AML cells. Moreover, cells treated with rapamycin resulted in a significant reduce of binding of YY1 to the αSMA promoter element in nuclear extracts of AML cells. Kidney angiomyolipoma tissues from TSC patients showed lower levels of tuberin and higher levels of phospho-p70S6K that resulted in higher levels of mRNA and protein of αSMA expression compared to control kidney tissues. In addition, most of the α-SMA staining was identified in the smooth muscle cells of AML tissues. YY1 was also significantly increased in tumor tissue of AMLs compared to control kidney tissue suggesting that YY1 plays a major role in the regulation of αSMA.. These data comprise the first report to provide one mechanism whereby rapamycin might inhibit the cell fibrosis in kidney tumor of TSC patients.

Topics: Actins; Cell Line; Enzyme Activation; Fibrosis; Gene Expression Regulation; Humans; Intracellular Space; Kidney Neoplasms; Models, Biological; Mutation; Promoter Regions, Genetic; Protein Binding; Protein Transport; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; YY1 Transcription Factor

Recent studies indicated that the tuberous sclerosis 2 (TSC2) gene product, tuberin, regulates Rac1 activity. However, the underlying mechanism by which tuberin regulates Rac1 activity has not been clearly elucidated to date. To better understand the molecular link between tuberin function and Rac1, we characterized the activity and distribution of Rac1 in mouse Tsc2-deficient renal tumor cells using restoration experiments with wild-type tuberin. Rac1 activity was significantly higher in tuberin-expressing cells compared with control Tsc2-deficient cells. Further, Rac1 activation was induced by rapamycin treatment or knockdown of raptor, but not rictor, in Tsc2-deficient cells, indicating that mTORC1 is an upstream negative regulator of Rac1. Intriguingly, Rac1 appeared to form cytoplasmic dots in Tsc2-deficient cells, but not in tuberin-expressing and since rapamycin treatment dispersed these dots, involvement of aberrant mTOR complex 1 (mTORC1) activation in the dot formation was suspected. Moreover, the dots were co-localized with p62/sequestosome-1 and ubiquitin. These findings imply that Rac1 distribution and/or its degradation may be regulated by tuberin through the mTORC1 signaling pathway.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antibiotics, Antineoplastic; Carrier Proteins; Cell Line, Tumor; Heat-Shock Proteins; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes; Neuropeptides; rac1 GTP-Binding Protein; Rapamycin-Insensitive Companion of mTOR Protein; Regulatory-Associated Protein of mTOR; RNA Interference; RNA, Small Interfering; Sequestosome-1 Protein; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factor TFIIH; Transcription Factors; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Ubiquitin

Topics: Benzenesulfonates; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Pyridines; Sirolimus

Topics: Angiomyolipoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lymphoma, T-Cell; Male; Middle Aged; Positron-Emission Tomography; Prednisone; Radiography; Sirolimus; Vincristine

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

The case pertains to a 47-year-old male. He consulted our institute regarding a tumor in his right kidney. Endoscopic retroperitoneal nephrectomy of the right kidney was conducted to remove the tumor. The postoperative pathology was Renal Cell Carcinoma (Clear cell carcinoma, pT1b, pNx, V (+), Fuhrman grade 4). Multiple lung metastases were observed upon CT scan the following year. Sunitinib was administered following Interferon alpha (IFN-alpha) therapy; however, the lung metastases became larger, so administration of everolimus at 10 mg/day was commenced. The lung metastatic lesion became smaller upon CT scan from 6 weeks following administration, and it was determined that the therapeutic effect was PR. The PR was still maintained upon CT scan 31 weeks following administration but the lung metastatic lesion still remained; therefore, right lower lobe resection and lymph node biopsy were conducted upon obtaining informed consent. The administration of everolimus at 10 mg/day is still subsequently being continued due to viable tumor cells being observed in the lung metastatic lesion and the lymph node. At present, 43 weeks have past since the start of everolimus administration, but no new metastatic lesions have been observed.

Topics: Carcinoma, Renal Cell; Endoscopy; Everolimus; Humans; Immunosuppressive Agents; Indoles; Interferon-alpha; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Nephrectomy; Pneumonectomy; Pyrroles; Sirolimus; Sunitinib; Tomography, X-Ray Computed; Treatment Failure; Treatment Outcome

We aimed to study key signalling proteins involved in angiogenesis and proliferation on the response to inhibitors of tyrosine kinases and mammalian target of rapamycin in first- and in second-line treatment of renal cell carcinoma (RCC).. In a panel of human RCC tumours, in vitro and in nude mice, we evaluated the effect of sunitinib, sorafenib and everolimus, alone and in sequence, on tumour growth and expression of signalling proteins involved in proliferation and resistance to treatment.. We demonstrated that, as single agents, sunitinib, sorafenib and everolimus share similar activity in inhibiting cell proliferation, signal transduction and vascular endothelial growth factor (VEGF) secretion in different RCC models, both in vitro and in tumour xenografts. Pre-treatment with sunitinib reduced the response to subsequent sunitinib and sorafenib but not to everolimus. Inability by sunitinib to persistently inhibit HIF-1, VEGF and pMAPK anticipated treatment resistance in xenografted tumours. After first-line sunitinib, second-line treatment with everolimus was more effective than either sorafenib or rechallenge with sunitinib in interfering with signalling proteins, VEGF and interleukin-8, translating into a significant advantage in tumour growth inhibition and mice survival.. We demonstrated that a panel of angiogenic and signalling proteins can correlate with the onset of resistance to sunitinib and the activity of everolimus in second line.

Topics: Angiogenesis Inhibitors; Angiogenic Proteins; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Growth Processes; Everolimus; Humans; Indoles; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrroles; Random Allocation; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; Xenograft Model Antitumor Assays

There is a new era of treatment options since introduction of new biological targeted therapies (tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors) in renal cell cancer. However, in patients who developed brain metastases, there is still treatment dilemma about an optimal therapeutic scenario, particularly in the subgroup of patients with-out disease progression outside the central nervous system. The objective of this case report is to present that it is possible to continue the same targeted therapy after development of brain metastasis after application of local whole brain irradiation with meaningful overall survival.

Topics: Aged; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Renal Cell; Disease Progression; Enzyme Inhibitors; Humans; Indoles; Kidney Neoplasms; Male; Protein-Tyrosine Kinases; Pyrroles; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome

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

Few studies have investigated the effects of everolimus therapy in Asian populations. This study evaluates the safety and efficacy of everolimus in Korean patients with metastatic renal cell carcinoma (mRCC).. We retrospectively reviewed records of Korean patients with mRCC (n = 22) who received everolimus between January 2009 and July 2010 and evaluated them for efficacy and safety.. One patient achieved a partial response, and 16 patients had stable disease, corresponding to an overall response rate of 4.5 % and a disease control rate of 77.3 %. Median progression-free survival was 5.4 months (95 % CI 0.9-9.8). Median overall survival was not reached. Univariate analysis showed that Memorial Sloan-Kettering Cancer Center risk (P = .004), thrombocytopenia (P = .018), hyperglycemia (P = .007) and hypertriglyceridemia (P = .041) were associated with disease progression. The most common adverse events (AEs) were hypertriglyceridemia and anemia, similar to Western patients. Creatinine and aspartate aminotransferase levels were higher than those reported for Western patients. The most common grade ≥3 AEs in this study were hypertriglyceridemia and anemia, compared with lymphopenia (14 %) in Western patients.. Safety of everolimus in Korean mRCC patients differed from that reported in Western patients. Therefore, liver function enzymes, hemoglobin levels, lipid profile and chest CT scans should be monitored more closely in Asian mRCC patients receiving everolimus.

Topics: Aged; Antineoplastic Agents; Asian People; Carcinoma, Renal Cell; Disease-Free Survival; Drug Monitoring; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Republic of Korea; Retrospective Studies; Sirolimus; Survival Rate; Treatment Outcome

A 56-year-old man was referred to our clinic because of left lumbar pain and a left solitary renal tumor (9. 8 cm in diameter) and bilateral pulmonary metastases detected by computed tomographic scan. Pathologic diagnosis following open radical nephrectomy was papillary renal cell carcinoma, G2, pT2aN0M1. Subsequently, the patient was sequentially treated with interleukin-2 (3 months (mo), progressive disease (PD)), interferon-alpha (3 mo, PD), and oral S-1 as a clinical trial (28 mo, PD). Because of skin fibrofolliculomas, pulmonary cysts, and spontaneous pneumothorax history, Birt-Hogg-Dubé (BHD) syndrome was suspected during the treatment course, despite his having no family history of the disease. Subsequent genetic testing revealed a FLCN germline mutation (c. 1285dupC). He was started on molecular-targeting therapies sequentially, i.e., sorafenib (1 mo, PD), sunitinib (4 mo, PD), and everolimus (7 mo, PD). The patient died of progressive disease at 78 mo from the initial nephrectomy and 30 mo from the start of targeted agents. Loss of FLCN function has been shown to result in the upregulation of the PI3K/mTORC1 pathway in both in vitro experiments and in vivo FLCN knockout mice models. Despite its use as the sixth-line systematic treatment, the mTOR inhibitor everolimus exhibited a relatively long-term effect as compared with the previously used tyrosine kinase inhibitors and in contrast to the results in the RECORD-1 clinical trial. This finding may provide insight into the molecular mechanism of BHDassociated renal tumors.

Topics: Animals; Antineoplastic Agents; Birt-Hogg-Dube Syndrome; Carcinoma, Renal Cell; Everolimus; Humans; In Vitro Techniques; Indoles; Kidney Neoplasms; Male; Mice, Knockout; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyrroles; Sirolimus; Sorafenib; Sunitinib

Topics: Antineoplastic Agents; Bone Neoplasms; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Liver Neoplasms; Male; Niacinamide; Phenylurea Compounds; Sirolimus

The aim of the study was to assess the safety and efficacy of everolimus therapy for advanced renal cell carcinoma in Japanese patients receiving real-world care.. Patients who had been treated with everolimus for advanced renal cell carcinoma at 39 Japanese medical centers between January 2010 and November 2011 were retrospectively investigated to assess adverse events and the time to treatment failure.. A total of 180 patients were identified. Their median age was 65 years (range 23-93). The median time to treatment failure was 2.9 months (95% confidence interval 2.4-3.4). The median time to treatment failure was significantly longer in patients with dose modification (4.2 months; 95% confidence interval 3.4-5.0) than in patients without dose modification (1.7 months; 95% confidence interval 1.0-2.3; P < 0.01) after experiencing adverse events. Stomatitis (44%) was the most frequent adverse event, followed by thrombocytopenia (31%), anemia (22%), interstitial pneumonia (22%) and hyperglycemia (17%). Interstitial pneumonia was the most frequent cause of discontinuation in patients who discontinued everolimus due to intolerability regardless of the dose modification status. None of the patients with dose modification of everolimus discontinued everolimus due to thrombocytopenia or leukopenia.. The adverse event profile of everolimus may differ between Japanese and Caucasian patients. Dose modification of everolimus might be associated with longer treatment duration in patients with advanced renal cell carcinoma. Further studies are required to clarify this association. Interstitial pneumonia may be difficult to overcome by dose modification.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Administration Schedule; Everolimus; Female; Humans; Hyperglycemia; Japan; Kaplan-Meier Estimate; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Retrospective Studies; Sirolimus; Stomatitis; Thrombocytopenia; Treatment Outcome

Everolimus is a mammalian target of rapamycin inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between pre-treatment neutrophil-to-lymphocyte ratio (NLR) and the outcome of patients treated with everolimus for mRCC.. Ninety-seven patients with mRCC were treated with everolimus till April 2013 in our institutions. Patients were stratified in two groups with NLR >3 (Group A) vs <3 (Group B). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Gender, age, Motzer prognostic group, PFS on first-line therapy, neutrophilia and NLR were included in the Cox analysis to investigate their prognostic relevance.. Median OS and PFS were 10.6 and 5.3 months, respectively. Median OS was 12.2 months in Group A and 24.4 months in Group B (P=0.001). Median PFS was 3.4 months in Group A and 9.9 months in Group B (P<0.001). At multivariate analysis, only Motzer prognostic group and NLR were independent prognostic factors for OS and PFS.. Pre-treatment NLR is an independent prognostic factor for patients with mRCC treated with second- or third-line everolimus. This should be investigated and validated in prospective studies.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Neoplasm Metastasis; Neutrophils; Sirolimus; Survival; TOR Serine-Threonine Kinases; Treatment Outcome

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 ideal sequence of targeted agents for advanced kidney cancer is still unknown. In the present study we assessed the clinical benefit of two different sequential approaches, namely sorafenib, an inhibitor of mammalian target of rapamycin (mTORi) and sunitinib, or sunitinib (an mTORi) and sorafenib.. we retrospectively reviewed the outcome of 40 advanced kidney cancer patients treated with one of the two above sequences.. a total of 26 patients were treated with the sequence sorafenib-mTORi-sunitinib and 14 with the sequence sunitinib-mTORi-sorafenib. The actuarial overall median progression-free survival (PFS) in the sorafenib-mTORi-sunitinib group and in the sunitinib-mTORi-sorafenib group were 21.9 and 22.8 months, respectively (log-rank test: p=0.928). In the sorafenib-mTORi-sunitinib group, patients in first-, second- and third-line therapy experienced PFS of 11.7, 5.1 and 9.1 months, respectively, while in the sunitinib-mTORi-sorafenib group PFS was 14.4, 4.3, and 3.9 months, respectively.. Our results suggest there is no significant difference between the two sequence modalities.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Everolimus; Female; Follow-Up Studies; Humans; Indoles; Kidney Neoplasms; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Prognosis; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases

New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had progressed on sunitinib and/or sorafenib. The only targeted therapy for mRCC currently reimbursed in Serbia is sunitinib.. The aim of this study was to estimate the cost-effectiveness and the budget impact of the introduction of everolimus in Serbia in comparison to best supportive care, for mRCC patients refractory to sunitinib.. A Markov model was designed corresponding with Serbian treatment protocols. A health care payer perspective was taken, including direct costs only. Treated and untreated cohorts were followed up over 18 cycles, each cycle lasting 8 weeks, which covered the lifetime horizon of mRCC patients refractory to the first-line treatment. Annual discounted rates of 1.5% for effectiveness and 3% for costs were applied. Transitions between health states were modeled by time-dependent probabilities extracted from published Kaplan-Meier curves of PFS and overall survival (OS). Utility values were obtained from the appraisals of other mRCC treatments. One-way and probabilistic sensitivity analyses were done to test the robustness and uncertainty of the base-case estimate. Lastly, the potential impacts of everolimus on the overall health care expenditures on annual and 4-year bases were estimated in the budget-impact analysis.. The incremental cost-effectiveness ratio for everolimus was estimated at €86,978 per quality-adjusted life-year. Sensitivity analysis identified the hazard multiplier, a statistical approximator of OS gain, as the main driver of everolimus cost-effectiveness. Furthermore, probabilistic sensitivity analyses revealed a wide 95% CI around the base-case incremental cost-effectiveness ratio estimate (€32,594-€425,258 per quality-adjusted life-year). Finally, an average annual budgetary impact of everolimus in first 4 years after its potential reimbursement would be around €270,000, contributing to <1% of the total budget in Serbian oncology.. Everolimus as a second-line treatment of mRCC is not likely to be a cost-effective option under the present conditions in Serbia, with a relatively limited impact on its budget in oncology. A major constraint on the estimation of the cost-effectiveness of everolimus relates to the uncertainty around the everolimus effect on extending OS. However, prior to a final decision on the acceptance/rejection of everolimus, reassessment of the whole therapeutic group might be needed to construct an economically rational treatment strategy within the mRCC field.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Cost-Benefit Analysis; Drug Costs; Everolimus; Health Care Costs; Humans; Indoles; Kidney Neoplasms; Markov Chains; Models, Economic; Pyrroles; Quality-Adjusted Life Years; Serbia; Sirolimus; Sunitinib; Survival Rate

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

AlphaB-crystallin (αB-crystallin), a small heat shock protein, has been reported to be involved in the growth, antiapoptosis, migration, and chemoresistance of human malignancies.. αB-crystallin expression in normal renal and clear cell renal cell carcinoma (ccRCC) tissues was examined with two-dimensional (2D) gel electrophoresis assays. Immunohistochemistry was conducted to determine the presence of αB-crystallin-positive tumor cells and staining intensity in 50 cases of ccRCC tissue samples. The association of αB-crystallin protein expression, clinicopathogic parameters and prognosis of ccRCC patients was also analyzed with Student's t-test and Kaplan-Meier analysis. Moreover, Western blot assays were performed to detect the protein expression of αB-crystallin in normal and tumor tissues and the alteration of cell cycle regulators in αB-crystallin-overexpressing cells. MTT (3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide), BrdU, and transwell assays were performed to demonstrate the effects of αB-crystallin overexpression on cell growth, DNA synthesis and cell migration of ccRCC cells, respectively.. The results showed the up-regulation of αB-crystallin expression in ccRCC tissues. Overall survival of ccRCC patients was significantly correlated with αB-crystallin expression in tumor tissues. We found that αB-crystallin overexpression increased the expression of cyclin A and the incorporation of BrdU, which may be related to the enhancement of cell growth. Transwell analyses demonstrated that presence of αB-crystallin overexpression enhanced cell migration in ccRCC cells. Furthermore, rapamycin-resistance of tumor cells was induced when αB-crystallin was overexpressed.. Our experimental findings highlight the importance of αB-crystallin in the tumor growth, migration, and target therapy-resistance of ccRCC cells.

Topics: Adult; Aged; Aged, 80 and over; alpha-Crystallin B Chain; Blotting, Western; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclin A; Disease Progression; Drug Resistance, Neoplasm; Electrophoresis, Gel, Two-Dimensional; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Multivariate Analysis; Prognosis; Proteomics; Sirolimus

Topics: Carcinoma, Renal Cell; Drug Therapy, Combination; Everolimus; Herpes Simplex; Herpesvirus 1, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Prednisolone; Sirolimus; Skin Diseases, Viral; Time Factors; Virus Activation

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

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

Topics: Adrenal Cortex Hormones; Amlodipine; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Calcium Channel Blockers; Carcinoma, Renal Cell; Drug Administration Schedule; Drug Interactions; Everolimus; Female; Humans; Kidney Neoplasms; Lisinopril; Middle Aged; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Biomarkers, Pharmacological; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; L-Lactate Dehydrogenase; Male; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

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

Epithelioid angiomyolipoma has malignant potential; however, no effective therapy has been established for advanced cases. A 50-year-old woman with a history of right nephrectomy for epithelioid angiomyolipoma was referred to our institution. Computed tomography and magnetic resonance imaging showed multiple tumors in her lung, liver and pelvic cavity. The liver and pelvic tumor specimens obtained by needle biopsy confirmed the diagnosis of epithelioid angiomyolipoma recurrence. The patient was treated with everolimus (10 mg/day). Three months later, pulmonary lesions disappeared; liver and pelvic tumors significantly shrank in size, but the pelvic tumor gradually enlarged again. We carried out surgical resection of the residual liver and pelvic cavity tumors. Although the mammalian target of rapamycin inhibitor seems to be effective for treating epithelioid angiomyolipoma, its long-term effects remain unknown. Thus, aggressive administration of a multidisciplinary treatment including molecular target therapy and surgical resection is required to improve the prognosis of epithelioid angiomyolipoma.

Topics: Angiomyolipoma; Everolimus; Female; Humans; Kidney Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

The tumor-suppressor genes TSC1 and TSC2 are mutated in tuberous sclerosis, an autosomal dominant multisystem disorder. The gene products of TSC1 and TSC2 form a protein complex that inhibits the signaling of the mammalian target of rapamycin complex1 (mTORC1) pathway. mTORC1 is a crucial molecule in the regulation of cell growth, proliferation and survival. When the TSC1/TSC2 complex is not functional, uncontrolled mTORC1 activity accelerates the cell cycle and triggers tumorigenesis. Recent studies have suggested that TSC1 and TSC2 also regulate the activities of Rac1 and Rho, members of the Rho family of small GTPases, and thereby influence the ensuing actin cytoskeletal organization at focal adhesions. However, how TSC1 contributes to the establishment of cell polarity is not well understood. Here, the relationship between TSC1 and the formation of the actin cytoskeleton was analyzed in stable TSC1-expressing cell lines originally established from a Tsc1-deficient mouse renal tumor cell line. Our analyses showed that cell proliferation and migration were suppressed when TSC1 was expressed. Rac1 activity in these cells was also decreased as was formation of lamellipodia and filopodia. Furthermore, the number of basal actin stress fibers was reduced; by contrast, apical actin fibers, originating at the level of the tight junction formed a network in TSC1-expressing cells. Treatment with Rho-kinase (ROCK) inhibitor diminished the number of apical actin fibers, but rapamycin had no effect. Thus, the actin fibers were regulated by the Rho-ROCK pathway independently of mTOR. In addition, apical actin fibers appeared in TSC1-deficient cells after inhibition of Rac1 activity. These results suggest that TSC1 regulates cell polarity-associated formation of actin fibers through the spatial regulation of Rho family of small GTPases.

Topics: Animals; Antibiotics, Antineoplastic; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Polarity; Cell Transformation, Neoplastic; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes; Neuropeptides; Proteins; rac GTP-Binding Proteins; rac1 GTP-Binding Protein; rho-Associated Kinases; Signal Transduction; Sirolimus; Stress Fibers; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

The incidence of native kidney renal cell carcinoma (RCC) in renal transplant recipients is 15 times higher than the general population. These tumors are often found incidentally when imaging is performed for another indication. At that stage tumors are usually small and asymptomatic but it is possible that they may escape detection until a more advanced stage. Early stage RCC can be treated with radical nephrectomy but the treatment of advanced RCC may be more complicated and is associated with a poorer prognosis. RCC in context of renal transplant presents a special therapeutic challenge; balancing treatment of a potentially lethal malignancy in a redundant organ whilst maintaining good allograft function.We describe 2 cases of advanced renal cell carcinoma of native kidneys in renal transplant recipients and present our experience with sirolimus as a dual immunosuppressive and anti-tumor agent.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Radiography; Sirolimus; TOR Serine-Threonine Kinases

Topics: Angiomyolipoma; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Nephrectomy; Sirolimus; TOR Serine-Threonine Kinases

Tuberous sclerosis complex (TSC) is a hamartoma syndrome in which brain, renal, and lung tumors develop and cause both morbidity and death. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1. Rapamycin and related drugs have been shown to have clinical benefit for these tumors in patients with TSC and those with sporadic forms of TSC-related neoplasms. However, lifelong therapy seems to be required, as tumors are not eliminated by this treatment. We examined the potential benefit of MLN0128, a novel potent mTOR ATP-competitive inhibitor, as a therapeutic strategy for renal cystadenomas that develop in A/J Tsc2(+/-) mice. Rapamycin given by intraperitoneal injection at 3 mg/kg 3 times per week, and MLN0128 given by gavage at 0.75 mg/kg 5 times per week had equivalent effects in suppressing tumor development during a 4-week treatment period, with an approximate 99% reduction in microscopic tumor cell volume. Marked reduction in activation of mTOR complex (mTORC)1 and blockade of cell growth was seen with both drugs, whereas only MLN0128 treatment had effects in blocking mTORC2 and 4EBP1 phosphorylation. However, when either drug was discontinued and mice were observed for two additional months, there was dramatic recovery of tumor growth, with extensive proliferation. Hence, longlasting tumor growth control is not achieved with transient treatment with either drug, and MLN0128 and rapamycin have equivalent therapeutic benefit in this mouse model. Differences in side-effect profiles might make MLN0128 more attractive for treatment of patients with TSC-related tumors, but will require additional study in humans.

Topics: Animals; Benzoxazoles; Cell Growth Processes; Cystadenoma; Disease Models, Animal; Immunohistochemistry; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Phosphorylation; Pyrimidines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Radiotherapy remains marginal in the treatment of renal cell carcinoma (RCC), due to radioresistance and risks of acute toxicity. However, recent data have shown that the m-TOR inhibitors could decrease the tumor resistance to ionizing radiation. At the same time, new highly conformal irradiation modalities may significantly improve the tolerance to radiation.. Here, we report the first case of concurrent use of mTOR antagonist, rapamycin and Helical Tomotherapy and its potential in critical organs sparing in a patient with retroperitoneal relapse from a RCC. He was treated with Everolimus, 10 mg/d and concurrent Helical Tomotherapy to the region of the recurrence (45 Gy, 1.8 Gy per fraction).. Helical Tomotherapy allowed very sharp dose distributions around the target volumes, while sparing critical organs from useless radiation. No radiotherapy related acute toxicity was observed. At last follow-up (6 months later), the patient remains in partial remission at the irradiated region.. While targeted agents might find applications for radiosensitizing purposes, this report highlights the potential of Helical Tomotherapy for reducing the doses delivered to the critical organs, thus improving tolerance to irradiation.

Topics: Aged; Combined Modality Therapy; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Radiotherapy, Intensity-Modulated; Sirolimus; Tomography, Spiral Computed; 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

Inhibition of the mammalian target of rapamycin (mTOR), a regulator of hypoxia inducible factor (HIF), is an established therapy for advanced renal cell cancer (RCC). Inhibition of mTOR results in compensatory AKT activation, a likely resistance mechanism. We evaluated whether addition of the Akt inhibitor perifosine to the mTOR inhibitor rapamycin would synergistically inhibit RCC.. Select RCC cell lines were studied [786-O, A498 (VHL mutant), CAKI-1 (VHL wild type), and 769-P (VHL methylated)] with single agent and combination therapy. Growth inhibition was assessed by MTT and cell cycling by flow cytometry. Phospho-AKT (S473) and HIF-2α were assessed by Western blot. Total RNA was isolated from 786-O cells subjected to single agent and combination treatments. In these cells, genome-wide expression profiles were assessed, and real-time PCR was used to confirm a limited set of expression results.. Three out of four cell lines (CAKI-1, 769-P, and 786-O) were sensitive to single-agent perifosine with 50% inhibitory concentrations ranging from 5 to 10 μM. Perifosine blocked phosphorylation of AKT induced by rapamycin and inhibited HIF-2α expression in 786-O and CAKI-1. Combined treatment resulted in sub-additive growth inhibition. GeneChip analysis and pathway modeling revealed inhibition of the IL-8 pathway by these agents, concomitant with up-regulation of the KLF2 gene, a known suppressor of HIF1α.. Perifosine is active in select RCC lines, abrogating the induction of AKT phosphorylation mediated by mTOR inhibition. Combined mTOR and AKT inhibition resulted in the modulation of pro-angiogenesis pathways, providing a basis for future investigations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Interleukin-8; Kidney Neoplasms; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Phosphorylation; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Male; Pyrroles; Sirolimus; Sunitinib

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

Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, there has been an increased interest in the use of antiangiogenic agents for the management of RCC in patients. However, the activity of tumor-vascular disrupting agents (tumor-VDA) has not been extensively examined against RCC. In this study, we investigated the therapeutic efficacy of the tumor-VDA ASA404 (DMXAA, 5,6-dimethylxanthenone-4-acetic acid, or vadimezan) in combination with the mTOR inhibitor everolimus (RAD001) against RCC. In vitro studies were carried out using human umbilical vein endothelial cells and in vivo studies using orthotopic RENCA tumors and immunohistochemical patient tumor-derived RCC xenografts. MRI was used to characterize the vascular response of orthotopic RENCA xenografts to combination treatment. Therapeutic efficacy was determined by tumor growth measurements and histopathologic evaluation. ASA404/everolimus combination resulted in enhanced inhibition of endothelial cell sprouting in the 3-dimensional spheroid assay. MRI of orthotopic RENCA xenografts revealed an early increase in permeability 4 hours posttreatment with ASA404, but not with everolimus. Twenty-four hours after treatment, a significant reduction in blood volume was observed with combination treatment. Correlative CD31/NG2 staining of tumor sections confirmed marked vascular damage following combination therapy. Histologic sections showed extensive necrosis and a reduction in the viable rim following combination treatment compared with VDA treatment alone. These results show the potential of combining tumor-VDAs with mTOR inhibitors in RCC. Further investigation into this novel combination strategy is warranted.

Topics: Angiogenesis Inhibitors; Animals; Antigens; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Everolimus; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Kidney Neoplasms; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Proteoglycans; Sirolimus; Spheroids, Cellular; TOR Serine-Threonine Kinases; Tumor Burden; Xanthones; Xenograft Model Antitumor Assays

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

Topics: Benzenesulfonates; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Pyridines; Sirolimus

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

Calcineurin inhibitors (CNIs) may promote post-transplantation cancer through altered expression of cytokines and chemokines in tumor cells. We found that there is a potential cross-talk among CNI-induced signaling molecules and mTOR. Here, we utilized a murine model of post-transplantation cancer to examine the effect of a combination therapy (CNI + mTOR-inhibitor rapamycin) on allograft survival and renal cancer progression. The therapy prolonged allograft survival; and significantly attenuated CNI-induced post-transplantation cancer progression, with down-regulation of mTOR and S6-kinase phosphorylation. Also, rapamycin inhibited CNI-induced over-expression of the angiogenic cytokine VEGF, and the chemokine receptor CXCR3 and its ligands in post-transplantation tumor tissues.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cell Line, Tumor; Chemokines; Down-Regulation; Drug Therapy, Combination; Enzyme Inhibitors; Graft Rejection; Graft Survival; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Mice; Neovascularization, Pathologic; Protein Kinase Inhibitors; Receptors, CXCR3; Sirolimus; TOR Serine-Threonine Kinases; Transplantation; Transplantation Tolerance; Transplantation, Homologous; Vascular Endothelial Growth Factor A

Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression.. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors.. Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).

Topics: Biomarkers, Tumor; Biopsy; Carcinoma, Renal Cell; Chromosome Aberrations; Everolimus; Evolution, Molecular; Exome; Genetic Heterogeneity; Humans; Immunosuppressive Agents; Kidney; Kidney Neoplasms; Mutation; Neoplasm Metastasis; Phenotype; Phylogeny; Ploidies; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Sirolimus

To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease.. Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treatment with everolimus.. Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tomography showed bilateral reticular and ground-glass opacities. Serum levels of lactate dehydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbronchial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was discontinued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormalities resolved within 2 months.. Serum Krebs von den Lungen 6 was elevated compared with baseline in all cases with interstitial lung disease. Some patients who developed mild interstitial lung disease during everolimus treatment could continue to receive the treatment. Even when severe interstitial lung disease developed, withdrawal of the drug and short-term use of high-dose steroids resulted in rapid recovery. Prompt recognition of interstitial lung disease exacerbation as well as exclusion of progressive disease or infection is of primary importance.

Topics: Aged; Antineoplastic Agents; Biomarkers; Biopsy; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Carcinoma, Renal Cell; Diagnosis, Differential; Disease Progression; Drug Administration Schedule; Everolimus; Female; Humans; Japan; Kidney Neoplasms; L-Lactate Dehydrogenase; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Mucin-1; Pulmonary Surfactants; Severity of Illness Index; Sirolimus; Tomography, X-Ray Computed

Topics: Acid Anhydride Hydrolases; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Gene Deletion; Humans; In Situ Hybridization, Fluorescence; Jejunal Neoplasms; Kidney Neoplasms; Male; Middle Aged; Neoplasm Proteins; Radiography; Sirolimus; Treatment Outcome; Von Hippel-Lindau Tumor Suppressor Protein

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by abnormal proliferation of immature smooth muscle cells and cystic lung destruction, which determines the prognosis of the disease. The kidney angiomyolipomas are usually very common in this disease and are usually asymptomatic unless complications arise. In the absence of a curative treatment, recent publications show promising results in molecular therapy to prevent functional decline and to control the size of the angiomyolipomas. These therapies include mTOR complex inhibitors, especially sirolimus. We report a case of a patient diagnosed with LAM who underwent lung transplantation with reduction of renal angiomyolipoma size after treatment with the mTOR inhibitor everolimus.

Topics: Adult; Angiomyolipoma; Antineoplastic Agents; Everolimus; Female; Humans; Kidney Neoplasms; Lung Transplantation; Lymphangioleiomyomatosis; Sirolimus; Tumor Burden

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

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

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

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

Chronic mTOR inhibition may induce resistance development in renal cell carcinoma (RCC). We analyzed whether long-term exposure of RCC cells to the mTOR-inhibitor RAD001 evokes resistance and whether additional targeting histone deacetylases (HDAC) by valproic acid (VPA) overcomes RAD001 resistance. It is demonstrated that responsiveness to either drug alone is lost over time, evidenced by increased cell growth, proliferation and de-differentiation. However, drug sensitivity was conserved when RAD001 and VPA were applied in concert. Molecular analysis particularly revealed strong re-activation of Akt under chronic RAD001 or diminished histone H3 acetylation under chronic VPA single drug exposure. Combined drug application did not inactivate Akt but rather resulted in H3 acetylation remaining high while RCC cell growth was still reduced. siRNA experiments revealed that histone H3 acetylation is responsible for preserving drug sensitivity in RCCs.

Topics: Acetylation; Apoptosis; Carcinoma, Renal Cell; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Everolimus; Histone Deacetylase Inhibitors; Histones; Humans; Kidney Neoplasms; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Valproic Acid

Topics: Abdominal Cavity; Acute Kidney Injury; Axitinib; Carcinoma, Renal Cell; Combined Modality Therapy; Everolimus; Humans; Imidazoles; Immunosuppressive Agents; Indazoles; Interferon-alpha; Kidney Neoplasms; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Nephrectomy; Protein Kinase Inhibitors; Remission Induction; Sirolimus; Tomography, X-Ray Computed; Withholding Treatment

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

Sequential treatment with targeted agents is standard of care for patients with metastatic renal cell carcinoma (mRCC). However, clinical data directly comparing treatment outcomes with a mammalian target of rapamycin inhibitor or a vascular endothelial growth factor-targeted agent in the second-line setting are lacking. We evaluated sequential treatment in a syngeneic, orthotopic mouse model of mRCC.. BALB/c mice were orthotopically implanted with murine RCC (RENCA) cells expressing luciferase and randomized to vehicle, sunitinib, sunitinib followed by sorafenib, or sunitinib followed by everolimus. Tumor growth and metastases were assessed by in vivo (whole body) and ex vivo (primary tumor, lung, liver) luciferase activity and necropsies, performed on day 20 or 46 for vehicle and treatment groups, respectively.. Sunitinib followed by everolimus was associated with reduced luciferase activity and primary tumor weight and volume compared with sunitinib, and sunitinib followed by sorafenib.. Sequential therapy with sunitinib followed by everolimus demonstrated significant antitumor and anti-metastatic effects.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Disease Models, Animal; Drug Administration Schedule; Everolimus; Female; Indoles; Kidney Neoplasms; Luciferases; Luminescent Measurements; Mice; Mice, Inbred BALB C; Pyrroles; Random Allocation; Sirolimus; Sunitinib

Tuberous sclerosis complex (TSC), an inherited tumor predisposition syndrome associated with mutations in TSC1 or TSC2, affects ∼1 in 6,000 individuals. Eighty percent of TSC patients develop renal angiomyolipomas, and renal involvement is a major contributor to patient morbidity and mortality. Recent work has shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition caused angiomyolipoma shrinkage but that this treatment may cause cytostatic not a cytotoxic effect. Endoplasmic reticulum (ER) stress can develop in TSC-associated cells due to mTORC1-driven protein translation. We hypothesized that renal angiomyolipoma cells experience ER stress that can be leveraged to result in targeted cytotoxicity. We used immortalized human angiomyolipoma cells stably transfected with empty vector or TSC2 (encoding tuberin). Using cell number quantification and cell death assays, we found that mTORC1 inhibition with RAD001 suppressed angiomyolipoma cell proliferation in a cytostatic manner. Angiomyolipoma cells exhibited enhanced sensitivity to proteasome inhibitor-induced ER stress compared with TSC2-rescued cells. After proteasome inhibition with MG-132, Western blot analyses showed greater induction of C/EBP-homologous protein (CHOP) and more poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavage, supporting ER stress-induced apoptosis. Live cell numbers also were decreased and cell death increased by MG-132 in angiomyolipoma cells compared with TSC2 rescued. Intriguingly, while pretreatment of angiomyolipoma cells with RAD001 attenuated CHOP and BiP induction, apoptotic markers cleaved PARP and caspase-3 and eukaryotic translation initiation factor 2α phosphorylation were increased, along with evidence of increased autophagy. These results suggest that human angiomyolipoma cells are uniquely susceptible to agents that exacerbate ER stress and that additional synergy may be achievable with targeted combination therapy.

Topics: Angiomyolipoma; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leupeptins; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Phosphorylation; Poly(ADP-ribose) Polymerases; Proteasome Inhibitors; Proteins; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factor CHOP; Transfection; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

The cytoprotective enzyme heme oxygenase-1 (HO-1) is often overexpressed in different types of cancers and promotes cancer progression. We have recently shown that the Ras-Raf-ERK pathway induces HO-1 to promote survival of renal cancer cells. Here, we examined the possible mechanisms underlying HO-1-mediated cell survival. Considering the growing evidence about the significance of apoptosis and autophagy in cancer, we tried to investigate how HO-1 controls these events to regulate survival of cancer cells. Rapamycin (RAPA) and sorafenib, two commonly used drugs for renal cancer treatment, were found to induce HO-1 expression in renal cancer cells Caki-1 and 786-O; and the apoptotic effect of these drugs was markedly enhanced upon HO-1 knockdown. Overexpression of HO-1 protected the cells from RAPA- and sorafenib-induced apoptosis and also averted drug-mediated inhibition of cell proliferation. HO-1 induced the expression of anti-apoptotic Bcl-xL and decreased the expression of autophagic proteins Beclin-1 and LC3B-II; while knockdown of HO-1 down-regulated Bcl-xL and markedly increased LC3B-II. Moreover, HO-1 promoted the association of Beclin-1 with Bcl-xL and Rubicon, a novel negative regulator of autophagy. Drug-induced dissociation of Beclin-1 from Rubicon and the induction of autophagy were also inhibited by HO-1. Together, our data signify that HO-1 is up-regulated in renal cancer cells as a survival strategy against chemotherapeutic drugs and promotes growth of tumor cells by inhibiting both apoptosis and autophagy. Thus, application of chemotherapeutic drugs along with HO-1 inhibitor may elevate therapeutic efficiency by reducing the cytoprotective effects of HO-1 and by simultaneous induction of both apoptosis and autophagy.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Proteins; Beclin-1; Benzenesulfonates; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Heme Oxygenase-1; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Membrane Proteins; Microtubule-Associated Proteins; Niacinamide; Phenylurea Compounds; Protoporphyrins; Pyridines; Sirolimus; Sorafenib

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

Topics: Aged; Angiomyolipoma; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lymphoma, Non-Hodgkin; Nephrectomy; Prednisone; Sarcoma, Kaposi; Sirolimus; Splenectomy; Tomography, X-Ray Computed; Vincristine

Topics: Aged; Antineoplastic Agents; Bronchial Neoplasms; Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Sirolimus

Renal angiomyolipoma in patients with tuberous sclerosis can cause life-threatening bleeding. Embolization or resection is recommended, but either intervention may result in substantial loss of renal function. Recently, regression of angiomyolipoma size has also been achieved with mTOR inhibitor therapy, but recurrent lesion growth after treatment cessation has to be expected. This is the first report on a multimodal therapeutic approach facilitating a nephron-sparing, definitive resection.. Three patients with renal angiomyolipoma not amenable to nephron-sparing surgery were treated with sirolimus aiming trough levels of 4-8 ng/ml. Treatment was well tolerated.. mTOR inhibitor treatment resulted in a regression of angiomyolipoma volume by 38-95 %. Thereafter, nephron-sparing angiomyolipoma resection conserved normal renal function.. Neoadjuvant use of mTOR inhibitor pretreatment may represent a novel approach facilitating nephron-sparing resection.

Topics: Angiomyolipoma; Antibiotics, Antineoplastic; Child; Female; Humans; Kidney Neoplasms; Male; Nephrectomy; Nephrons; Sirolimus; Tuberous Sclerosis; Young Adult

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Renal Dialysis; 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

Treatment with everolimus is known to prolong progression-free survival in patients with renal cell carcinoma resistant against tyrosine-kinase inhibitor therapy. The side effects must be known for more effective use of this drug. Information of side effects was collected from a randomized controlled study, the early post-marketing phase vigilance and from our own experience. Interstitial lung disease (ILD) was a potentially severe side effect. Incidence of ILD was relatively large compared with that of other target therapy agents. Infections, thrombocytopenia, stomatitis and others were experienced as other side effects. However, there were few uncontrollable side effects. Management of side effects of everolimus can be improved by obtaining sufficient knowledge.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Sirolimus

Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. A 58-year-old woman was treated with everolimus as a third-line therapy for metastatic clear-cell renal carcinoma. She was given oral everolimus 10 mg once daily. During the fourth week of her first cycle, the patient was admitted to our hospital because of an acute-onset, right upper quadrant pain associated with nausea and vomiting. She was diagnosed with acute cholecystitis, which was treated with broad-spectrum antibiotics, and everolimus therapy was discontinued. A follow-up computed tomography scan of the abdomen revealed a complete resolution of gallbladder changes. Our patient did not have major risk factors for developing a cholecystitis except for a relative immunosuppressed state secondary to her advanced renal cancer. The Naranjo adverse drug reaction probability scale score for this event was 5, indicating a probable association of the event with everolimus. Because the use of everolimus is expanding in clinical practice, we want to alert the oncology community about this uncommon and life-threatening complication in patients receiving everolimus or another agent with antiangiogenic activity. To our best knowledge, only one case of an acute cholangitis associated with everolimus in a metastatic renal cell carcinoma has been reported. We report herein the first case of a metastatic renal cell carcinoma developed everolimus-associated cholecystitis that was completely reversed after drug withdrawal.

Topics: Administration, Oral; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Cholecystitis, Acute; Everolimus; Female; Humans; Kidney Neoplasms; Middle Aged; Protein Kinase Inhibitors; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome

Long-term stabilization of advanced renal cell carcinoma (RCC) by the sequence of sorafenib monotherapy followed by sunitinib and everolimus treatments in a man with multiple metastases is reported. A 66-year-old man was diagnosed with advanced RCC in 2005. The patient initially underwent nephrectomy, but subsequently the disease metastasized to the lung, lymph nodes, and pancreas. The patient received sorafenib 400 mg bid in a clinical trial. He experienced minimal and manageable adverse events and achieved stable disease (SD), which was maintained with sorafenib therapy for nearly 3 years before the development of liver metastases. The patient was then prescribed sunitinib, with which he also experienced SD for 1.2 years until disease progression prompted the initiation of third-line everolimus therapy, resulting in SD for another 8 months. The patient lived with stabilized RCC for 4.6 years with the use of these three sequential targeted therapies. First-line sorafenib monotherapy achieved a durable stable response and subsequent use of sunitinib and then everolimus permitted a return to SD after disease progression. The patient experienced minimal toxicity from the regimen, suggesting that it can be safely administered to elderly patients.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Everolimus; Humans; Indoles; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib

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

A 70-year-old man with metastatic renal cell carcinoma developed progressive liver metastases after 8 weeks of treatment with the multitargeted tyrosine kinase inhibitor (TKI) sunitinib. He then participated in the phase III placebo-controlled clinical trial of the oral mammalian target of rapamycin (mTOR) inhibitor everolimus, initially randomized to placebo (but had disease progression after 3 months) and crossed over to everolimus at time of unblinding. The patient had stable disease after 8 weeks (two cycles) of everolimus that was maintained until 28 months of therapy, at which time the patient had achieved a partial response. This case illustrates the potential for patients with metastatic renal cell carcinoma, a malignancy with historically poor prognosis, to derive long-term benefit from everolimus when used in a manner consistent with its approved indication (after TKI therapy with sunitinib or sorafenib).

Topics: Aged; Antineoplastic Agents; Arthritis, Rheumatoid; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Everolimus; Humans; Hypercholesterolemia; Hypertension; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Pyrroles; Randomized Controlled Trials as Topic; Salvage Therapy; Sirolimus; Sunitinib

Animal models are instrumental in understanding disease pathophysiology and mechanisms of therapy action and resistance in vivo.. To establish and characterize a panel of mouse models of renal cell carcinoma (RCC) derived from patients undergoing radical nephrectomy.. In vivo and in vitro animal experiments.. Tumor tissues obtained during surgery were implanted into the subcutaneous space of female BALB/c nude mice and serially passaged into new mice. Tumors were characterized by histology, short tandem repeat (STR) fingerprinting, von Hippel-Lindau (VHL) gene sequencing, and single nucleotide polymorphism (SNP) analysis. Tumor-bearing mice were treated with sunitinib or everolimus. Primary cell cultures were derived from patient tumors and transfected with a lentivirus carrying the luciferase gene. Four subcutaneous xenograft mouse models were developed, representing papillary type 1, papillary type 2, clear cell, and clear cell with sarcomatoid features RCC.. RCC mouse models were established from four patients with distinct histologies of RCC. Tumor growth was dependent on histologic type, the size of the implanted tumor chip, and the passage number. Mouse tumors accurately represented their respective original patient tumors, as STR fingerprints were matching, histology was comparable, and SNP profiles and VHL mutation status were conserved with multiple passages. Bioluminescence imaging results were commensurate with subcutaneous xenograft growth patterns. Mice treated with sunitinib and everolimus exhibited an initial response, followed by a later stage of resistance to these agents, which mimics the clinical observations in patients with RCC.. We developed four mouse xenograft models of RCC with clear-cell and papillary histologies, with stable histologic and molecular characteristics. These models can be used to understand the basic biology of RCC as well as response and resistance to therapy.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Models, Animal; DNA Fingerprinting; Everolimus; Female; Humans; Immunosuppressive Agents; Indoles; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Polymorphism, Single Nucleotide; Pyrroles; Sirolimus; Sunitinib; Transfection; Tumor Cells, Cultured; von Hippel-Lindau Disease; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Kidney Transplantation; Lung Neoplasms; Middle Aged; Niacinamide; Phenylurea Compounds; Pyridines; Sirolimus; Sorafenib

Brit-Hogg-Dubé (BHD) syndrome, an autosomal dominant familial cancer, is associated with increased risk of kidney cancer. BHD syndrome is caused by loss-of-function mutations in the folliculin (FLCN) protein. To develop therapeutic approaches for renal cell carcinoma (RCC) in BHD syndrome, we adopted a strategy to identify tumor-selective growth inhibition in a RCC cell line with FLCN inactivation. The COMPARE algorithm was used to identify candidate anticancer drugs tested against the NCI-60 cell lines that showed preferential toxicity to low FLCN expressing cell lines. Fifteen compounds were selected and detailed growth inhibition (SRB) assays were done in paired BHD RCC cell lines (UOK257 derived from a patient with BHD). Selective sensitivity of FLCN-null over FLCN-wt UOK257 cells was observed in seven compounds. The most selective growth-inhibitory sensitivity was induced by mithramycin, which showed an approximately 10-fold difference in GI(50) values between FLCN-null (64.2 ± 7.9 nmol/L, n = 3) and FLCN-wt UOK257 cells (634.3 ± 147.9 nmol/L, n = 4). Differential ability to induce caspase 3/7 activity by mithramycin was also detected in a dose-dependent manner. Clonogenic survival studies showed mithramycin to be approximately 10-fold more cytotoxic to FLCN-null than FLCN-wt UOK257 cells (200 nmol/L). Following mithramycin exposure, UOK257-FLCN-null cells were mainly arrested and blocked in S and G(2)-M phases of the cell cycle and low dose of rapamycin (1 nmol/L) potentiated mithramycin sensitivity (1.5-fold in G(2)-M population and 2-fold in G(2)-M period time, 2xGI(50), 48 hours). These results provide a basis for further evaluation of mithramycin as a potential therapeutic drug for RCC associated with BHD.

Topics: Algorithms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, p53; Genes, Tumor Suppressor; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Plicamycin; Proto-Oncogene Proteins; PTEN Phosphohydrolase; Sirolimus; Tumor Suppressor Proteins

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Pyrroles; Sirolimus; Sunitinib; 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

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

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

Traditional phase III non-inferiority trials require compelling evidence that the treatment vs control effect bfθ is better than a pre-specified non-inferiority margin θ(NI) . The standard approach compares this margin to the 95 per cent confidence interval of the effect parameter. In the phase II setting, in order to declare Proof of Concept (PoC) for non-inferiority and proceed in the development of the drug, different criteria that are specifically tailored toward company internal decision making may be more appropriate. For example, less evidence may be needed as long as the effect estimate is reasonably convincing. We propose a non-inferiority design that addresses the specifics of the phase II setting. The requirements are that (1) the effect estimate be better than a critical threshold θ(C), and (2) the type I error with regard to θ(NI) is controlled at a pre-specified level. This design is compared with the traditional design from a frequentist as well as a Bayesian perspective, where the latter relies on the Level of Proof (LoP) metric, i.e. the probability that the true effect is better than effect values of interest. Clinical input is required to establish the value θ(C), which makes the design transparent and improves interactions within clinical teams. The proposed design is illustrated for a non-inferiority trial for a time-to-event endpoint in oncology.

Topics: Antineoplastic Agents; Bayes Theorem; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Confidence Intervals; Everolimus; Humans; Indoles; Kidney Neoplasms; Pyrroles; Research Design; Sirolimus; Sunitinib

Topics: Carcinoma, Renal Cell; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Middle Aged; Oncology Nursing; Pneumonia; Sirolimus

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

Everolimus is the standard second-line therapy for patients with metastatic renal cell carcinoma (mRCC). We evaluated whether the response to first-line therapy with a tyrosine kinase inhibitor (TKI) has predictive impact on the progression-free survival (PFS) and overall survival (OS) under everolimus. In addition, patient characteristics were evaluated for their predictive impact on the response under everolimus.. 42 patients with mRCC treated with everolimus (RAD001) within a clinical trial were analyzed. Prior to everolimus, every patient had received at least 1 TKI therapy. Another TKI for second line was given to 15 patients. PFS and OS were estimated according to the Kaplan-Meier method and compared with the log-rank test.. Median PFS during everolimus therapy was 5.2 months (range 1.3-17.8). 27 patients (64%) achieved stable disease (SD) or partial remission (PR). Patients with a beneficial PFS under first-line TKI achieved a better OS after start of everolimus treatment (p = 0.05) and so did TKI responders (p = 0.04). A reduced OS was associated with liver metastases (p = 0.04) and high tumor burden (p = 0.01).. A beneficial outcome under prior TKI therapy is predictive for a superior survival in patients treated with everolimus, while high tumor burden and liver metastases impair the OS.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Germany; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Prevalence; Risk Assessment; Risk Factors; Sex Distribution; Sirolimus; Survival Analysis; Survival Rate; Treatment Outcome

Malignant epithelioid variant of angiomyolipoma has aggressive characteristics, against which conventional cytotoxic agents have been reported to be disappointingly inactive, and the prognosis of unresectable or recurrent disease is dismal poor. A 52-year-old man with a history of left nephrectomy for epithelioid angiomyolipoma was referred to our institution. The computed tomographic scan showed a soft tissue dense mass around the Rex's recess and behind the spleen, and a large pelvic mass. Specimens obtained by percutaneous needle biopsy confirmed the recurrence of malignant epithelioid angiomyolipoma. Everolimus was initiated at 10 mg per day for recurrent disease. Computed tomographic scans 2 months later showed the tumors to be markedly decreased in size. The patient has continued with this treatment on an outpatient basis without signs of disease progression over 7 months, as of February 2011. In this case, treatment with everolimus resulted in dramatic tumor response for the malignant epithelioid variant of angiomyolipoma.

Topics: Administration, Oral; Angiomyolipoma; Antineoplastic Agents; Epithelioid Cells; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Positron-Emission Tomography; Recurrence; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases

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

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 14-year-old girl with metastatic renal cell carcinoma was treated with nephrectomy, interferon, and several lines of the targeted agents sorafenib, bevacizumab, sunitinib, and everolimus, either alone or in combination. Treatment was well tolerated, but the patient developed hypothyroidism and significant hypertension with bevacizumab and sunitinib. She responded to all agents and was given radiation treatment twice at the time of symptomatic disease progression; she died 33 months from diagnosis.

Topics: Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Combined Modality Therapy; Everolimus; Fatal Outcome; Female; Humans; Kidney Neoplasms; Nephrectomy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Sirolimus; Sorafenib

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

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: Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Mycophenolic Acid; Sirolimus; Tacrolimus

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

Topics: Antineoplastic Agents; Benzimidazoles; Carcinoma, Renal Cell; Everolimus; Humans; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrroles; Quinolones; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Topics: Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Receptors, Vascular Endothelial Growth Factor; Sirolimus

The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined.. To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment.. Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres.. Sequence of systemic targeted treatment with sunitinib (n=85) or sorafenib (n=23) followed by EV (n=62) or another rTKI (n=46; sorafenib, n=35; sunitinib, n=11).. We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS).. Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8-5.4) for EV and 4.0 mo (3.2-4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9-52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6-39.5; p=0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15-3.62; p=0.015) and OS (HR: 6.54; 95% CI, 3.01-14.20; p<0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors.. The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.

Topics: Academic Medical Centers; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Chi-Square Distribution; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Everolimus; Female; Germany; Humans; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Proportional Hazards Models; Protein Kinase Inhibitors; Pyridines; Pyrroles; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Sorafenib; Sunitinib; Survival Rate; Time Factors; Treatment Failure

Topics: Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Disease Management; Everolimus; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Sirolimus; Treatment Failure

PI3K and mTOR are key components of signal transduction pathways critical for cell survival. Numerous PI3K inhibitors have entered clinical trials, while mTOR is the target of approved drugs for metastatic renal cell carcinoma (RCC). We characterized expression of p85 and p110α PI3K subunits and mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules in vitro.. We employed tissue microarrays containing 330 nephrectomy cases using a novel immunofluorescence-based method of Automated Quantitative Analysis (AQUA) of in situ protein expression. In RCC cell lines we assessed synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235, which co-targets PI3K and mTOR.. p85 expression was associated with high stage and grade (P < 0.0001 for both). High p85 and high mTOR expression were strongly associated with decreased survival, and high p85 was independently prognostic on multi-variable analysis. Strong co-expression of both PI3K subunits and mTOR was found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were highly synergistic in all six RCC cell lines studied. Similar synergism was seen with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in vitro with IC(50)s in the low ηM range and resultant PARP cleavage.. High PI3K and mTOR expression in RCC defines populations with decreased survival, suggesting that they are good drug targets in RCC. These targets tend to be co-expressed, and co-targeting these molecules is synergistic. NVP-BEZ235 is active in RCC cells in vitro; suggesting that concurrent PI3K and mTOR targeting in RCC warrants further investigation.

Topics: Apoptosis; Automation; Biomarkers, Tumor; Carcinoma, Renal Cell; Cell Line, Tumor; Chromones; Drug Synergism; Humans; Imidazoles; Inhibitory Concentration 50; Kidney Neoplasms; Molecular Targeted Therapy; Morpholines; Multivariate Analysis; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Quinolines; Sirolimus; 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

Malignancy is a major problem in patients treated with immunosuppressive agents. We have demonstrated that treatment with calcineurin inhibitors (CNIs) can induce the activation of proto-oncogenic Ras, and may promote a rapid progression of human renal cancer through the overexpression of vascular endothelial growth factor (VEGF). Interestingly, we found that CNI-induced VEGF overexpression and cancer cell proliferation was inhibited by rapamycin treatment, indicating potential involvement of the mammalian target of rapamycin (mTOR) pathway in this tumorigenic process. Here, we examined the role of mTOR pathway in mediating CNI- and Ras-induced overexpression of VEGF in human renal cancer cells (786-0 and Caki-1). We found that the knockdown of raptor (using siRNA) significantly decreased CNI-induced VEGF promoter activity as observed by promoter-luciferase assay, suggesting the role of mTOR complex1 (mTORC1) in CNI-induced VEGF transcription. It is known that mTOR becomes activated following phosphorylation of its negative regulator PRAS40, which is a part of mTORC1. We observed that CNI treatment and activation of H-Ras (through transfection of an active H-Ras plasmid) markedly increased the phosphorylation of PRAS40, and the transfection of cells using a dominant-negative plasmid of Ras, significantly decreased PRAS40 phosphorylation. Protein kinase C (PKC)-ζ and PKC-δ, which are critical intermediary signaling molecules for CNI-induced tumorigenic pathway, formed complex with PRAS40; and we found that the CNI treatment increased the complex formation between PRAS40 and PKC, particularly (PKC)-ζ. Inhibition of PKC activity using pharmacological inhibitor markedly decreased H-Ras-induced phosphorylation of PRAS40. The overexpression of PRAS40 in renal cancer cells significantly down-regulated CNI- and H-Ras-induced VEGF transcriptional activation. Finally, it was observed that CNI treatment increased the expression of phosho-PRAS40 in renal tumor tissues in vivo. Together, the phosphorylation of PRAS40 is critical for the activation of mTOR in CNI-induced VEGF overexpression and renal cancer progression.

Topics: Adaptor Proteins, Signal Transducing; Calcineurin Inhibitors; Cell Line, Tumor; Humans; Kidney Neoplasms; Phosphorylation; ras Proteins; Sirolimus; TOR Serine-Threonine Kinases; Transcription, Genetic; Vascular Endothelial Growth Factor A

Therapy of patients with metastatic renal cell carcinoma (mRCC) requires sequential use of several agents with different mechanisms and minimal cross-resistance between the different agents. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free survival (PFS) in patients with mRCC. Re-challenge with TKIs provides clinical benefit after everolimus in patients with mRCC. We report the case of an mRCC patient with lung and bone metastases, treated sequentially with sunitinib, sorafenib and everolimus. The patient had an objective response in reducing bone metastases, but adaptative and concomitant progression in lung metastases during sunitinib re-challenge. Previously, these lung metastases had responded to sunitinib. This intriguing paradox suggests that not only was sunitinib able to target a specific metastatic site during the re-challenge, as seen by the reduction of bone metastases, but it also elicited a more invasive adaptation and progression of lung tumor cells.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indoles; Kidney Neoplasms; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrroles; Radiography; Sirolimus; Sunitinib

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

Everolimus is an oral mTOR kinase inhibitor approved for the treatment of patients with metastatic renal cell carcinoma (mRCC) progressing during or after treatment with vascular endothelial growth factor (VEGF)-targeted agents. Using the national RENIS clinical registry, we have retrospectively analysed outcomes of patients treated for mRCC with everolimus. A total of 78 patients were evaluable. Median progression-free survival from the start of everolimus therapy was 7 months (95% confidence interval 2-12 months). Partial response or stable disease was achieved in 69% of patients. Treatment toxicity was predictable and serious adverse events occurred in only 6% of patients the most common being respiratory toxicity. Everolimus therapy provides significant clinical benefit for heavily pretreated mRCC patients after failure of VEGF-targeted therapy.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

We report the case of a 25-year-old woman who presented with abdominal and flank pain with two successive pregnancies and was diagnosed of giant bilateral renal AMLs and pulmonary LAM associated with TSC in the post-partum of her second pregnancy. This case illustrates that in women with TSC rapid growth from renal AMLs and development of LAM may occur with successive pregnancies. It also stresses the potential for preservation of renal function despite successive bilateral renal surgery of giant AMLs. Moreover, the treatment with a low-dose rapamycin may be an option for LAM treatment. Finally, a low-dose rapamycin may be considered as an adjuvant treatment together to kidney-sparing conservative surgery for renal AMLs.

Topics: Adult; Angiomyolipoma; Female; Humans; Kidney Neoplasms; Lymphangioleiomyomatosis; Pregnancy; Pregnancy Complications, Neoplastic; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

We herein report two cases of everolimus-associated interstitial pneumonia in patients with renal cell carcinoma. A 68-year-old Japanese man (case 1) was admitted to our hospital because of progressive dyspnea, left infiltration and consolidation on chest radiographs. He had started receiving everolimus (10 mg daily) three months before the admission for the treatment of recurrent renal cell carcinoma. Bronchoalveolar lavage fluid taken from his left B(4) showed a marked increase of lymphocytes (42.9%). An organizing pneumonia pattern of everolimus-associated interstitial pneumonia was strongly suspected radiologically, and treatment with high-dose corticosteroids, discontinuation of everolimus and oxygen support was started. The treatment was successful, and the patient recovered with only minor pulmonary fibrotic changes in the left lower lobe. A 57-year-old Japanese man (case 2) was referred to our department for the evaluation of interstitial pneumonia. He had started to receive everolimus (10 mg daily) four months previously. Chest CT demonstrated interstitial pneumonia predominantly in bilateral lower lobes, with small pulmonary metastatic nodules. His pulmonary complications were spontaneously resolved eight days after the discontinuation of everolimus. To the best of our knowledge, Case 1 is the first reported case of successfully treated organizing pneumonia pattern of interstitial pneumonia with acute respiratory failure induced by everolimus in Japan.

Topics: Adrenal Cortex Hormones; Aged; Carcinoma, Renal Cell; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Radiography; Respiratory Insufficiency; Sirolimus

Hyperactivation of the PI3K/AKT/mTOR signaling pathway is common in cancer, and PI3K and mTOR act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of PI3K and mTOR presents an opportunity for robust and synergistic anticancer efficacy. 17-Hydroxywortmannin (2a) analogues conjugated to rapamycin (3a) analogues via a prodrug linker are uniquely positioned for this approach. Our efforts led to the discovery of diester-linked conjugates that, upon in vivo hydrolysis, released two highly potent inhibitors. Conjugate 7c provided enhanced solubility relative to 3a and to an equivalent mixture of 3a and 9a and demonstrated profound activity in U87MG mouse xenografts, achieving an MED of 1.5 mg/kg, following weekly intravenous dosing. At 15 mg/kg, 7c completely inhibited the growth of HT29 tumors, whereas an equivalent mixture of the inhibitors was poorly tolerated. In the A498 renal tumor model, 7c exhibited superior efficacy over 3a or 9a when administered as a single agent or in combination with bevacizumab. Thus, we have uncovered a novel approach to target both PI3K and mTOR via hybrid inhibitors, leading to a broader and more robust anticancer efficacy.

Topics: Androstadienes; Animals; Antineoplastic Agents; Drug Design; Drug Stability; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Mice; Mice, Nude; Molecular Conformation; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Rats; Sirolimus; Stereoisomerism; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Wortmannin; Xenograft Model Antitumor Assays

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

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

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cholestasis; Drug Resistance, Neoplasm; Everolimus; Humans; Kidney Neoplasms; Neoplasm Metastasis; Protein Kinase Inhibitors; Salvage Therapy; Sirolimus

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

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

Topics: Angioedema; Anti-Allergic Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Diphenhydramine; Epinephrine; Everolimus; Humans; Kidney Neoplasms; Male; Methylprednisolone; Middle Aged; Sirolimus; Tongue Diseases

A male with tuberous sclerosis complex (TSC) developed a chest wall fibromatosis and bilateral multifocal renal cell carcinoma (RCC). The fibromatosis tumor was initially resected during infancy but recurred 5 years later. At that time, bilateral RCC was also detected, leading to the resection of the more extensively affected right kidney. In an attempt to avoid bilateral nephrectomies, the patient was treated with the mTOR inhibitor sirolimus. Within 6 months of therapy, the fibromatosis and remaining RCC tumors responded substantially with minimal adverse effects.

Topics: Antibiotics, Antineoplastic; Carcinoma, Renal Cell; Child; Fibroma; Humans; Kidney Neoplasms; Loss of Heterozygosity; Male; Sirolimus; Thoracic Wall; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor disorder characterized by the growth of hamartomas in various organs including the kidney, brain, skin, lungs, and heart. Rapamycin has been shown to reduce the size of kidney angiomyolipomas associated with TSC; however, tumor regression is incomplete and kidney angiomyolipomas regrow after cessation of treatment. Mouse models of TSC2 related tumors are useful for evaluating new approaches to drug therapy for TSC.. In cohorts of Tsc2+/- mice, we compared kidney cystadenoma severity in A/J and C57BL/6 mouse strains at both 9 and 12 months of age. We also investigated age related kidney tumor progression and compared three different rapamycin treatment schedules in cohorts of A/J Tsc2+/- mice. In addition, we used nude mice bearing Tsc2-/- subcutaneous tumors to evaluate the therapeutic utility of sunitinib, bevacizumab, vincristine, and asparaginase.. TSC related kidney disease severity is 5-10 fold higher in A/J Tsc2+/- mice compared with C57BL/6 Tsc2+/- mice. Similar to kidney angiomyolipomas associated with TSC, the severity of kidney cystadenomas increases with age in A/J Tsc2+/- mice. When rapamycin dosing schedules were compared in A/J Tsc2+/- cohorts, we observed a 66% reduction in kidney tumor burden in mice treated daily for 4 weeks, an 82% reduction in mice treated daily for 4 weeks followed by weekly for 8 weeks, and an 81% reduction in mice treated weekly for 12 weeks. In the Tsc2-/- subcutaneous tumor mouse model, vincristine is not effective, but angiogenesis inhibitors (sunitinib and bevacizumab) and asparaginase are effective as single agents. However, these drugs are not as effective as rapamycin in that they increased median survival only by 24-27%, while rapamycin increased median survival by 173%.. Our results indicate that the A/J Tsc2+/- mouse model is an improved, higher through-put mouse model for future TSC preclinical studies. The rapamycin dosing comparison study indicates that the duration of rapamycin treatment is more important than dose intensity. We also found that angiogenesis inhibitors and asparaginase reduce tumor growth in a TSC2 tumor mouse model and although these drugs are not as effective as rapamycin, these drug classes may have some therapeutic potential in the treatment of TSC related tumors.

Topics: Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Asparaginase; Bevacizumab; Cystadenoma; Disease Models, Animal; Drug Administration Schedule; Female; Indoles; Kidney Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Pyrroles; Sirolimus; Sunitinib; Survival Rate; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Vincristine

Xp11 translocation renal cell carcinoma (RCC) is an RCC subtype affecting 15% of RCC patients <45 years. We analyzed the benefit of targeted therapy [vascular endothelial growth factor receptor (VEGFR)-targeted agents and/or mammalian target of rapamycin (mTOR) inhibitors] in these patients.. Patients with Xp11 translocation/TFE3 fusion gene metastatic RCC who had received targeted therapy were identified. Nuclear TFE3 positivity was confirmed by reviewing pathology slides. Responses according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed.. Overall, 53 patients were identified; 23 had metastatic disease, and of these 21 had received targeted therapy (median age 34 years). Seven patients achieved an objective response. In first line, median PFS was 8.2 months [95% confidence interval (CI) 2.6-14.7 months] for sunitinib (n = 11) versus 2 months (95% CI 0.8-3.3 months) for cytokines (n = 9) (log-rank P = 0.003). Results for further treatment (second, third, or fourth line) were as follows: all three patients receiving sunitinib had a partial response (median PFS 11 months). Seven of eight patients receiving sorafenib had stable disease (median PFS 6 months). One patient receiving mTOR inhibitors had a partial response and six patients had stable disease. Median OS was 27 months with a 19 months median follow-up.. In Xp11 translocation RCC, targeted therapy achieved objective responses and prolonged PFS similar to those reported for clear-cell RCC.

Topics: Adolescent; Adult; Antineoplastic Agents; Antiviral Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Benzenesulfonates; Carcinoma, Renal Cell; Child; Child, Preschool; Chromosomes, Human, Pair 11; Chromosomes, Human, X; Everolimus; Female; Gene Fusion; Humans; Immunosuppressive Agents; Indoles; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Research Report; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Translocation, Genetic; Treatment Outcome; Vascular Endothelial Growth Factor A; Young Adult

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

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

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Data Interpretation, Statistical; Disease-Free Survival; Everolimus; Evidence-Based Medicine; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Neoplasm Staging; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Research Design; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome

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 medical treatment of renal-cell carcinoma, and of its most frequent subtype, clear cell renal-cell carcinoma, has recently been drastically changed by the emergence of targeted therapies. The development of these drugs has been made possible by more precise knowledge of molecular mechanisms involved in the carcinogenesis of these tumors. We present in this article the molecular pathways linked to targeted therapies for clear cell renal-cell carcinoma: VHL/HIF/VEHF and PI3K/AkT/mTOR pathways. We also describe succinctly the EGFR pathways, and the molecular mechanisms involved in other histological subtypes. Then, we briefly describe how these targeted therapies work. We finally discuss how biology could improve the use of these therapies, by developing new prognostic factors, and predictive factors of response to treatment.

Topics: Carcinoma, Renal Cell; Carrier Proteins; Cytoskeletal Proteins; ErbB Receptors; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Molecular Chaperones; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Drug Interactions; Everolimus; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sirolimus; Sulfonamides

Tuberous sclerosis, caused by germline mutations in the TSC1 or TSC2 genes, is associated with aberrant upregulation of the mammalian target of rapamycin (mTOR) signalling pathway, resulting in growth of tumours, including renal angiomyolipomas (AMLs). AMLs may cause hypertension, renal failure and spontaneous life-threatening haemorrhage. Previously, invasive interventions were required to treat AMLs. More recently, mTOR inhibitors have been used as molecularly targeted treatment to treat AMLs. We present here the case of a paediatric patient with TSC in whom sirolimus has been used successfully to halt growth of renal AMLs.

Topics: Angiomyolipoma; Antibiotics, Antineoplastic; Child; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Sirolimus; Tuberous Sclerosis

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

The high incidence of cancer and its aggressive progression is a common and major problem in patients receiving immunosuppressive therapy. The calcineurin inhibitors (CNIs) may have protumorigenic effects and can promote the overexpression of several molecules inducing tumor growth. We have recently demonstrated that CNIs can mediate the transcriptional activation of the angiogenic cytokine vascular endothelial growth factor (VEGF) and promote a rapid progression of human renal cancer. Here, we investigated whether the CNI cyclosporine (CsA) and the mTOR inhibitor rapamycin (RAPA) could alter the mRNA stability of VEGF in 786-0 and Caki-1 renal cancer cells. Following actinomycin D treatment, we observed that CsA increased, whereas RAPA decreased the VEGF mRNA stability as observed by real time PCR. It is established that the mRNA-binding protein HuR may play a critical role in VEGF mRNA stability. By using HuR-siRNA, we found that the knockdown of HuR significantly decreased the CNI-induced VEGF mRNA stability. By Western blot analysis, it has been observed that CNI treatment induced the translocation of HuR from the nucleus to the cytoplasm; CNIs also induced the association between HuR and PKC-delta and promoted the phosphorylation of HuR. Finally, we found that the inhibition of PKC-delta using a dominant negative plasmid significantly decreased the CsA-induced cytoplasmic translocation of HuR and VEGF mRNA stability. Together, targeting the pathways that promote CNI-induced transcription as well as the mRNA stability of VEGF might serve as novel therapeutics for the prevention and treatment of cancer in immunosuppressed patients.

Topics: Antigens, Surface; Blotting, Western; Cell Line, Tumor; Cyclosporine; ELAV Proteins; ELAV-Like Protein 1; Humans; Immunoprecipitation; Immunosuppressive Agents; Kidney Neoplasms; Protein Binding; Protein Kinase C-delta; Protein Transport; RNA Stability; RNA-Binding Proteins; Sirolimus; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Drug Approval; Everolimus; Humans; Indoles; Kidney Neoplasms; Practice Guidelines as Topic; Pyrroles; Sirolimus; Sunitinib; United Kingdom

Inhibitors of TORC1 have been shown to be active in patients with metastatic renal cell carcinoma (RCC). As the phosphatidylinositol 3-kinase (PI3K) pathway activates numerous other kinases, transcription factors, and proteins associated with cell growth and survival besides mammalian target of rapamycin (mTOR), disruption of this pathway upstream of mTOR may be more effective than inhibition of TORC1 alone.. To investigate this possibility, the dual PI3K/mTOR inhibitor NVP-BEZ235 was compared with rapamycin in RCC cell lines and xenografts generated from 786-O and A498 cells.. Treatment of RCC cell lines with NVP-BEZ235 in vitro resulted in the nuclear translocation of p27, greater reduction in tumor cell proliferation, and more complete suppression of Akt, Mnk-1, eIF4E, and 4EBP-1 phosphorylation and cyclin D1 and hypoxia-inducible factor 2alpha (HIF2alpha) expression than that achieved with rapamycin. The reduction of HIF2alpha levels correlated with reduced HIF activity as determined by luciferase assay. NVP-BEZ235 induced growth arrest in both the 786-O and A498 xenografts that was associated with inhibition of Akt and S6 phosphorylation as well as the induction of apoptosis and reduction in markers of tumor cell proliferation. In contrast, rapamycin induced only minimal growth retardation.. Dual inhibition of PI3K/mTOR with NVP-BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone. These results provide the rationale for the clinical assessment of agents such as NVP-BEZ235 in patients with advanced RCC.

Topics: Animals; Carcinoma, Renal Cell; Cell Death; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Enzyme Inhibitors; Female; Humans; Imidazoles; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Nude; Multiprotein Complexes; Neoplasm Transplantation; Phosphoinositide-3 Kinase Inhibitors; Proteins; Quinolines; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors; Xenograft Model Antitumor Assays

Inhibition of mTOR by rapamycin is an important approach in cancer therapy. In early clinical trials, tuberous sclerosis complex (TSC)-related kidney tumours were found to regress following rapamycin treatment. Since loss of function of the DNA repair OGG1 enzyme has a major role in multistep carcinogenesis of the kidney and other organs, we investigated the effect of rapamycin on OGG1 regulation. Treatment of HK2 cells, mouse Tsc-deficient cells and human VHL-deficient cells (786-O) with rapamycin resulted in decrease in p70S6K phosphorylation at Thr(389), and increase in the expression of NF-YA and OGG1 proteins. In addition, rapamycin increased OGG1 promoter activity in cells transfected with OGG1 promoter construct. Furthermore, rapamycin increased the phosphorylation at Thr(172) of the energy sensor AMPK. Downregulation of AMPK phosphorylation by high glucose (HG) increases the phosphorylation of p70S6K and decreases the protein expression of NF-YA and OGG1. Pretreatment of the cells with rapamycin before exposure to HG reversed the effects of HG. However, downregulation of AMPK by dominant negative (DN)-AMPK in Tsc2(+/-) cells abolished AMPK and decreased OGG1 expression. In contrast, transfection of Tsc2(+/-) cells with DN-S6K abolished p70S6K phosphorylation and increased OGG1 expression, a response enhanced by rapamycin. Treatment of Tsc2(+/-) mice with rapamycin resulted in activation of AMPK, downregulation of phospho-p70S6K and enhanced OGG1 expression. Our data show that inhibition of mTOR can activate AMPK and lead to upregulation of DNA repair enzyme OGG1. These data comprise the first report to provide one mechanism whereby rapamycin might prevent or inhibit the formation and progression of certain cancers.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Antibiotics, Antineoplastic; DNA Glycosylases; DNA Repair Enzymes; Drug Screening Assays, Antitumor; Epithelial Cells; Humans; Immunoblotting; Kidney Neoplasms; Kidney Tubules, Proximal; Male; Mice; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Up-Regulation

Tuberous sclerosis complex (TSC) is caused by constitutively activated mammalian target of rapamycin (mTOR) resulting in non-malignant tumours of several organs including renal angiomyolipomas (AMLs). AMLs may originate renal failure, hypertension and spontaneous life-threatening bleeding. Recent reports suggest a possible beneficial role of the mTOR inhibitor rapamycin for TSC. However, safety and efficiency of rapamycin in TSC patients as an anti-proliferative agent are still undefined. A 40-year-old man with sporadic TSC and a history of spontaneous bleeding from his left kidney AMLs received low-dose rapamycin for 12 months, and this was associated with a reduction in bilateral kidney AML volume, stabilization and even improvement of renal function. There was also a reduction of facial angiofibromas, improvement of blood pressure control and absence of AML bleeding over this time period. Brain lesion images remained stable, and no significant rapamycin-associated side effects were noted. To the best of our knowledge, this is the first report of a case of reduction in renal AML volume together with preservation of renal function in a patient with TSC receiving low-dose rapamycin. These data suggest that it could be the result of the anti-angiogenic, anti-fibrotic and anti-proliferative effects of rapamycin.

Topics: Adult; Angiomyolipoma; Humans; Kidney; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Topics: Antineoplastic Agents; Humans; Kidney Neoplasms; Sirolimus; Survival Analysis

The mammalian target of rapamycin (mTOR) is an important therapeutic target in the treatment of renal cell carcinoma (RCC). Pre-clinical data indicate that the combined inhibition of both the epidermal growth factor receptor and mTOR results in enhanced anticancer activity.. All patients had metastatic RCC with progression after treatment with sunitinib and/or sorafenib. Treatment consisted of erlotinib 150 mg orally once a day starting on day 1 and sirolimus 6 mg orally on day 8 followed by 2 mg daily, adjusted according to blood levels.. A total of 25 patients were enrolled between July 2006 and March 2008. The median progression-free survival (PFS) was 12 weeks (95% CI 5.9-18.1) and median overall survival (OS) 40 weeks (95% CI 0-85.7). No confirmed complete or partial responses were observed, but stable disease >6 months was noted in 21.8% (95% CI 4.9-38.6) of patients. The most common adverse events were rash and diarrhoea. There was no correlation between erlotinib, OSI-420 (days 8 and 15) or sirolimus (days 15 and 29) blood levels and PFS or OS.. The combination of sirolimus and erlotinib for RCC failed to demonstrate an advantage over available single-agent therapy in the second-line setting.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Chromatography, Liquid; Disease-Free Survival; Erlotinib Hydrochloride; Female; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib; Tandem Mass Spectrometry

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

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Sirolimus; Vascular Endothelial Growth Factor A

Tuberous sclerosis complex (TSC) is an inherited multisystem disorder; it may involve kidney, brain, skin, lungs, and liver. We report a 37-year-old female TSC patient presenting with skin lesions (angiofibromas, molluscum pendulum). Radiologic examination revealed additional brain and renal lesions consisting of tumors, cysts, and angiomyolipomas. Treatment with rapamycin disclosed improvement in skin lesions. The number and volume of angiofibromas and molluscum pendulum reduced progressively in 6 months. During the ninth month of treatment, magnetic resonance imaging was repeated for renal and brain lesions. Imaging results showed reduction in tumor and angiomyolipoma volumes. Oral rapamycin therapy can improve renal, brain, and skin lesions in TSC disease. Therefore, it may be an alternative therapy for TSC patients.

Topics: Adult; Angiofibroma; Brain Neoplasms; Facial Neoplasms; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Magnetic Resonance Imaging; Sirolimus; Skin Neoplasms; Tuberous Sclerosis

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

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

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

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

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by hamartomatous growths in the brain, skin, kidneys, lungs, and heart, which lead to significant morbidity. TSC is caused by mutations in the TSC1 or TSC2 genes, whose products, hamartin and tuberin, form a tumor suppressor complex that regulates the PI3K/Akt/mTOR pathway. Early clinical trials show that TSC-related kidney tumors (angiomyolipomas) regress when treated with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (also known as sirolimus). Although side effects are tolerable, responses are incomplete, and tumor regrowth is common when rapamycin is stopped. Strategies for future clinical trials may include the investigation of longer treatment duration and combination therapy of other effective drug classes.. Here, we examine the efficacy of a prolonged maintenance dose of rapamycin in Tsc2+/- mice with TSC-related kidney tumors. Cohorts were treated with rapamycin alone or in combination with interferon-gamma (IFN-g). The schedule of rapamycin included one month of daily doses before and after five months of weekly doses. We observed a 94.5% reduction in kidney tumor burden in Tsc2+/- mice treated (part one) daily with rapamycin (8 mg/kg) at 6 months

Topics: Animals; Atorvastatin; Benzenesulfonates; Cystadenoma; Disease Models, Animal; Doxycycline; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Heptanoic Acids; Immunosuppressive Agents; Interferon-gamma; Kidney Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Neoplasms, Experimental; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrroles; Sirolimus; Sorafenib; Survival Analysis; Treatment Outcome; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Burden; Tumor Suppressor Proteins

Nowadays cancer represents the second main cause of death in renal transplant patients with normal function of the graft. The incidence is 10 to 20 times higher than normal population. Calcineurin inhibitor therapy contributes to the increase in the development of neoplasia. Important evidence could bring a preventive effect of mammalian target of rapamycin in skin cancer, Kaposi's sarcoma, and renal cell carcinoma.

Topics: Aged; Calcineurin Inhibitors; Carcinoma, Renal Cell; Cause of Death; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Neoplasms; Postoperative Complications; Protein Kinases; Risk Factors; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

Topics: Administration, Oral; Animals; Carcinoma, Renal Cell; Drug Approval; Everolimus; Humans; Kidney Neoplasms; Sirolimus

Tuberous sclerosis complex (TSC) is an autosomal-dominant disease that is caused by mutations in either the TSC1 or TSC2 gene. Smooth muscle-like cells (ASMs) were isolated from an angiomyolipoma of a patient with TSC. These cells lacked tuberin, were labeled by both HMB45 and CD44v6 antibodies, and had constitutive S6 phosphorylation. The cells bear a germline TSC2 intron 8-exon 9 junction mutation, but DNA analysis and polymerase chain reaction amplification failed to demonstrate loss of heterozygosity. Testing for an epigenetic alteration, we detected methylation of the TSC2 promoter. Its biological relevance was confirmed by tuberin expression and a reduction in HMB45 labeling and S6 constitutive phosphorylation after exposure to the chromatin-remodeling agents, trichostatin A and 5-azacytidine. These cells were named TSC2(-/meth) ASMs. Their proliferation required epidermal growth factor in the medium as previously described for TSC2(-/-) ASMs. Blockade of epidermal growth factor with monoclonal antibodies caused the death of TSC2(-/meth) ASMs. In addition, rapamycin effectively blocked the proliferation of these cells. Our data show for the first time that methylation of the TSC2 promoter might cause a complete loss of tuberin in TSC2 cells, and that the pathogenesis of angiomyolipomas might also originate from epigenetic defects in smooth muscle cells. Additionally, the effect of chromatin-remodeling agents in these cells suggests a further avenue for the treatment of TSC as well as lymphangioleiomyomatosis.

Topics: Adult; Angiomyolipoma; Antibiotics, Antineoplastic; Antigens, Neoplasm; Apoptosis; Blotting, Western; Cell Proliferation; DNA Methylation; DNA Mutational Analysis; Germ-Line Mutation; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Kidney Neoplasms; Male; Melanoma-Specific Antigens; Microscopy, Fluorescence; Myocytes, Smooth Muscle; Neoplasm Proteins; Promoter Regions, Genetic; Sirolimus; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Expression of the type 1 insulin-like growth factor receptor (IGF1R) confers adverse prognosis in clear cell renal cell cancer (CC-RCC). We recently showed that IGF1R expression is inhibited by the von Hippel-Lindau (VHL) tumor suppressor, and the IGF1R is up-regulated in CC-RCC, in which VHL is frequently inactivated. We tested the hypothesis that IGF1R up-regulation mediates resistance to cancer therapeutics, evaluating the effects of IGF1R depletion on sensitivity to cytotoxic drugs, which are ineffective in RCC, and the mammalian target of rapamycin (mTOR) inhibitor rapamycin, analogues of which have clinical activity in this tumor.. This study used CC-RCC cells harboring mutant VHL, and isogenic cells expressing functional VHL. Cells were transfected with nonsilencing control small interfering RNA (siRNA), or with one of two different IGF1R siRNAs. The more potent siRNA was modified by 2'-O-methyl derivatization for in vivo administration.. CC-RCC cells expressing mutant VHL and higher IGF1R were more chemoresistant than cells expressing functional VHL. IGF1R depletion induced apoptosis, blocked cell survival, and sensitized to 5-fluorouracil and etoposide. These effects were significantly greater in CC-RCC cells expressing mutant VHL, supporting the hypothesis that IGF1R up-regulation makes a major contribution to the chemoresistance associated with VHL loss. IGF1R depletion also enhanced sensitivity to mTOR inhibition, at least in part due to suppression of rapamycin-induced Akt activation. Administration of stabilized IGF1R siRNA was shown to sensitize CC-RCC xenografts to rapamycin in vivo.. These data validate IGF1R as a therapeutic target in CC-RCC, and support the evaluation of IGF1R-inhibitory drugs in patients with renal cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Etoposide; Female; Fluorouracil; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, SCID; Receptor, IGF Type 1; RNA, Small Interfering; Sirolimus; Transfection; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays

Tuberous sclerosis (TSC) is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus) leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235.. Using ENU to enhance Tsc2+- kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week) and NVP-BEZ235 (45 mg/kg PO QD) had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation.. Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.

Topics: Animals; Antineoplastic Agents; Carrier Proteins; Disease Models, Animal; Ethylnitrosourea; Everolimus; Imidazoles; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiprotein Complexes; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphotransferases (Alcohol Group Acceptor); Proteins; Quinolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors; Tuberous Sclerosis

In participants of the CONVERT trial, which enrolled recipients of kidney transplants, conversion of immunosuppressive therapy from calcineurin inhibitors to sirolimus did not improve renal function. More importantly, the intervention was detrimental among patients with impaired kidney function and/or proteinuria. Sirolimus conversion resulted, however, in lower rates of malignancy.

Topics: Calcineurin Inhibitors; Delayed Graft Function; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Neoplasms; Kidney Transplantation; Proteinuria; Sirolimus

Topics: Carcinoma, Renal Cell; Drug Discovery; Everolimus; Humans; Kidney Neoplasms; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

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

Malignancy is a dreaded complication following organ transplantation. Immunosuppressive therapy-induced impairment of the host immune system is the prevailing hypothesis for the high incidence and aggressive progression of post-transplant neoplasm. We summarize our observations supporting an autonomous cellular mechanism for cyclosporine and tacrolimus associated metastases. Cyclosporine conferred tumor invasiveness by a direct effect on the tumor cells and promoted metastases in T-, B-, and NK cell deficient SCID- beige mice, and anti-TGF-beta antibodies reduced metastases. Tacrolimus, another calcineurin inhibitor widely used in transplantation, induced TGF-beta secretion by tumor cells and promoted metastases in the SCID- beige mice. The immunosuppressive macrolide rapamycin reversed an invasive phenotype to a non-invasive one, reduced circulating levels of TGF-beta1 and prevented tumor growth and metastases in the immocompetant BALB/c mice and in the SCID-beige mice. Our studies, in addition to demonstrating a cell autonomous mechanism for tumor progression, advance TGF-beta blockade as an anti-tumor strategy.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line, Tumor; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, SCID; Neoplasm Invasiveness; Neoplasms; Organ Transplantation; Phenotype; Sirolimus; Tacrolimus

Everolimus is an orally administered, targeted therapy indicated for the treatment of advanced renal cell carcinoma. It inhibits the mammalian target of rapamycin, an integral component of multiple pathways involved in cell growth and proliferation. Median progression-free survival was significantly longer with everolimus 10 mg once daily than with placebo in both second interim (4.0 vs 1.9 months) and updated (4.9 vs 1.9 months) analyses of a randomized, double-blind, placebo-controlled, multicentre, phase III trial in patients with metastatic renal cell carcinoma that had progressed while receiving sunitinib and/or sorafenib treatment. At the second interim analysis, median overall survival was 8.8 months for placebo recipients; at this analysis, overall survival had not yet been reached for everolimus recipients. With regard to objective response at the second interim analysis, 64% of everolimus and 32% of placebo recipients had either a partial response (1% and 0%) or stable disease (63% and 32%). The tolerability profile of everolimus was largely manageable in the phase III trial, with most treatment-related adverse events being of grade 1 or 2 severity.

Topics: Benzenesulfonates; Carcinoma, Renal Cell; Cell Proliferation; Clinical Trials, Phase III as Topic; Disease-Free Survival; Double-Blind Method; Everolimus; Humans; Immunosuppressive Agents; Indoles; Kidney Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Placebos; Protein Kinase Inhibitors; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

A 26-year-old woman with lymphangioleiomyomatosis (LAM) was hospitalized for the surgical excision of a giant abdominal tumor of right kidney origin. The pathological diagnosis of the tumor was conventional angiomyolipoma (AML). After 8 months, 2 liver tumors appeared and grew rapidly. The tumors were resected, and the pathological finding of these tumors was epithelioid AML. Thereafter, metastatic multiple lung tumors appeared, and there was local recurrence of the liver tumors. Sirolimus, an mTOR protein inhibitor, was used to treat epithelioid AML. However, the drug did not inhibit the rapid growth of the tumor at all. This finding suggests that sirolimus might not be effective against epithelioid AML, and in such cases, complete surgical resection should be the treatment of choice.

Topics: Adult; Angiomyolipoma; Fatal Outcome; Female; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphangioleiomyomatosis; Neoplasm Recurrence, Local; Sirolimus

Topics: Biological Availability; Carcinoma, Renal Cell; Drug Interactions; Everolimus; Humans; Kidney Neoplasms; Oncology Nursing; Patient Education as Topic; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Topics: Acute Kidney Injury; Antineoplastic Agents; Carcinoma; Humans; Kidney Neoplasms; Male; Middle Aged; Sirolimus

Topics: Aged; Antibiotics, Antineoplastic; Biopsy, Needle; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Humans; Immunohistochemistry; Kidney Neoplasms; Laparoscopy; Liver Neoplasms; Lung Neoplasms; Male; Neoplasm Staging; Nephrectomy; Palliative Care; Quality of Life; Risk Assessment; Sirolimus; Treatment Outcome

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Sirolimus

Topics: Antineoplastic Agents; Brachytherapy; Carcinoma, Renal Cell; Clinical Trials as Topic; Deoxycytidine; Endometrial Neoplasms; Everolimus; Female; Gemcitabine; Humans; Kidney Neoplasms; Male; Pancreatic Neoplasms; Sirolimus

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Biomarkers; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Cross-Over Studies; Disease-Free Survival; Everolimus; Humans; Immunosuppressive Agents; Kidney Neoplasms; Predictive Value of Tests; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Survival Analysis

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

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Immunosuppressive Agents; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

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

von Hippel-Lindau (VHL) disease is a genetic syndrome based on an abnormality of the VHL gene located on the short arm of chromosome 3. Clinically, it presents as multiple tumors at several levels. The VHL gene product (pVHL) acts as a tumor-suppressing protein. In conditions of hypoxia it leads to an increase in several growth factor levels. mTOR inhibitors have proved to have dual properties: immunosuppressive and antitumor effects. Herein we have presented a case in which conversion to sirolimus improved graft function and also caused regression of retinal angioblastomas.

Topics: Adenocarcinoma; Humans; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Renal Dialysis; Sirolimus; Treatment Outcome; von Hippel-Lindau Disease

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

Patients with Birt-Hogg-Dubé (BHD) syndrome harbor germline mutations in the BHD tumor suppressor gene that are associated with an increased risk for kidney cancer. BHD encodes folliculin, a protein that may interact with the energy- and nutrient-sensing 5'-AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling pathways.. We used recombineering methods to generate mice with a conditional BHD allele and introduced the cadherin 16 (KSP)-Cre transgene to target BHD inactivation to the kidney. Kidney cell proliferation was measured by BrdU incorporation and phospho-histone H3 staining. Kidney weight data were analyzed with Wilcoxon's rank-sum, Student's t, and Welch's t tests. Hematoxylin and eosin staining and immunoblot analysis and immunohistochemistry of cell cycle and signaling proteins were performed on mouse kidney cells and tissues. BHD knockout mice and kidney cells isolated from BHD knockout and control mice were treated with the mTOR inhibitor rapamycin. Mouse survival was evaluated by Kaplan-Meier analyses. All statistical tests were two-sided.. BHD knockout mice developed enlarged polycystic kidneys and died from renal failure by 3 weeks of age. Targeted BHD knockout led to the activation of Raf-extracellular signal-regulated protein kinase (Erk)1/2 and Akt-mTOR pathways in the kidneys and increased expression of cell cycle proteins and cell proliferation. Rapamycin-treated BHD knockout mice had smaller kidneys than buffer-treated BHD knockout mice had (n = 4-6 mice per group, relative kidney/body weight ratios, mean = 4.64% vs 12.2%, difference = 7.6%, 95% confidence interval = 5.2% to 10.0%; P < .001) and longer median survival time (n = 4-5 mice per group, 41.5 vs 23 days; P = .0065 ).. Homozygous loss of BHD may initiate renal tumorigenesis in the mouse. The conditional BHD knockout mouse may be a useful research model for dissecting multistep kidney carcinogenesis, and rapamycin may be considered as a potential treatment for Birt-Hogg-Dubé syndrome.

Topics: Animals; Antibiotics, Antineoplastic; Blotting, Southern; Cell Proliferation; Disease Models, Animal; Estrone; Fluorescent Antibody Technique; Gene Silencing; Genotype; Germ-Line Mutation; Immunoblotting; Immunohistochemistry; Kaplan-Meier Estimate; Kidney; Kidney Neoplasms; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Polycystic Kidney Diseases; Protein Kinases; Proto-Oncogene Proteins; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sirolimus; Syndrome; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

To determine the role of hypoxia-inducible factor-2alpha (HIF2alpha) on the sensitivity of renal cell carcinoma (RCC) cell lines to ionizing radiation and to determine if the mTOR antagonist, rapamycin, could decrease HIF2alpha protein levels.. Cell lines expressing stable short-hairpin RNAs (shRNAs) encoding HIF2alpha shRNAs or an empty vector were transfected with a hypoxia responsive element (HRE)-driven firefly luciferase reporter gene. Two separate paired cell lines were assayed for their response to increasing doses of ionizing radiation. Proliferation and cell cycle kinetics were compared for cell lines expressing HIF2alpha shRNAs and empty vectors. The effect of an mTOR antagonist, rapamycin on HIF1alpha and HIF2alpha proteins levels was also assessed.. We confirmed that the 786-O RCC lines with stably integrated shRNAs against HIF2alpha had decreased activation of a plasmid with a HRE-driven firefly luciferase reporter gene. Lines from two separate cell clones with decreased HIF2alpha levels showed a significant increase in radiation sensitivity and an increase in G2 cell cycle arrest. Rapamycin, while effective in decreasing HIF1alpha protein levels, did not affect HIF2alpha levels in either of the RCC cell lines.. These results show that decreasing levels of HIF2alpha leads to an increased sensitivity to ionizing radiation. This finding may explain in part, the known resistance of RCC to radiation therapy. Although mTOR antagonists are approved for the treatment of RCC, these agents do not decrease HIF2alpha levels and therefore might not be effective in enhancing the radio-sensitivity of these tumours.

Topics: Antibiotics, Antineoplastic; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Carcinoma, Renal Cell; Cell Death; Cell Line, Tumor; Cell Proliferation; Flow Cytometry; G2 Phase; Genes, Reporter; Humans; Kidney Neoplasms; Luciferases; Protein Kinases; Radiation Tolerance; Radiation-Sensitizing Agents; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Sirolimus

The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC) is associated with frequent treatment failures (approximately 90% in metastatic cases), and these tumors frequently contain PTEN abnormalities.. Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis.. Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories.

Topics: Animals; Apoptosis; Base Sequence; Cisplatin; Cyclin-Dependent Kinase Inhibitor p21; Cytosol; DNA Damage; Dogs; Down-Regulation; Enzyme Activation; Humans; Kidney Neoplasms; Molecular Sequence Data; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; RNA Interference; Sirolimus

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

To test the hypothesis that blockage of epidermal growth factor receptor (EGFR) or methylethylketone (MEK)1/2 kinase activities impairs the growth of kidney cancer cells and magnifies the growth inhibitory effect of the mammalian target of rapamycin (mTOR) inhibitor rapamycin.. The kidney cancer cells from eight cell lines (including a pair in which the VHL gene or an empty vector was transfected in a VHL(mut) cell line) were tested for the effect of treatment with an EGFR inhibitor or an MEK1/2 inhibitor on the phosphorylation status of the phosphatidyl inositol 3-OH kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways after stimulation with EGF. In vitro growth assays were performed with EGFR inhibitors (gefitinib or erlotinib) or with MEK1/2 inhibitors (UO126 or PD184352) alone or in combination with rapamycin. The effects of PD184352, rapamycin, and their combination in the cell cycle were evaluated by flow cytometry.. The growth suppressive effect of combined gefitinib (or erlotinib) and rapamycin was greater than the effect of each drug alone and was not dependent on VHL status. By affecting downstream signaling, the MEK1/2 inhibitors U0126 and PD184352 blocked growth more effectively than did the EGFR inhibitors in selected renal cell carcinoma lines; this effect was enhanced by the addition of rapamycin. At the cell cycle level, the combination resulted in enhanced G1 arrest. Although eIF4E overexpression has been suggested to make cells resistant to rapamycin, we observed marked growth inhibition with rapamycin as a single agent in SKRC39, which has marked overexpression of eIF4E.. The results of our study have shown that combined mTOR and other upstream inhibitors have strong potential in the treatment of renal cell carcinoma.

Topics: Antibiotics, Antineoplastic; Benzamides; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma, Renal Cell; Cell Cycle; ErbB Receptors; Erlotinib Hydrochloride; Flow Cytometry; Gefitinib; Kidney Neoplasms; Mitogen-Activated Protein Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Quinazolines; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

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

Topics: Basilar Artery; Brain Infarction; Cerebellum; Cerebral Arteries; Disease Progression; Emphysema; Female; Headache; Hemianopsia; Humans; Hypertension; Immunosuppressive Agents; Intracranial Hemorrhage, Hypertensive; Kidney Neoplasms; Lung Transplantation; Magnetic Resonance Imaging; Middle Aged; Occipital Lobe; Posterior Cerebral Artery; Sirolimus

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

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

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

Tumor-derived endothelial cells (TEC) display increased survival and angiogenic properties in respect to normal endothelial cells. The aim of this study was to investigate the mechanism potentially involved in TEC proangiogenic phenotype. We found that thrombospondin-1 (TSP-1), a potent physiological inhibitor of angiogenesis, was significantly reduced in TEC in respect to normal endothelial cells. This reduction was confirmed by immunofluorescence in the intratumor vessels of clear cell renal carcinomas. As TEC were shown to display a basal upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, we evaluated the possible regulation of TSP-1 by this pathway by using LY294002 and wortmannin, the PI3K inhibitors, and rapamycin, the mammalian target of rapamycin (mTOR) inhibitor. In addition, we developed negative dominant TEC for Akt. TSP-1 production by TEC was enhanced by the treatment with LY294002 and wortmannin and with rapamycin, suggesting a negative regulation of TSP-1 expression by the PI3K/Akt/mTOR pathway. In addition, downregulation of Akt activation in negative dominant Akt TEC enhanced TSP-1 expression and release. Administration of exogenous TSP-1 to TEC reduced their proangiogenic properties in vitro and in vivo. In parallel, blockade of TSP-1 with an anti-TSP-1 antibody in negative dominant Akt TEC restored their proangiogenic phenotype to levels similar to wild-type TEC. In conclusion, these results indicate that the upregulation of the PI3K/Akt/mTOR pathway is responsible for the inhibition of TSP-1 synthesis which is critical in determining the proangiogenic phenotype of TEC. Strategies aimed to inhibit the PI3K/Akt/mTOR pathway may restore a normal quiescent endothelial phenotype in TEC by promoting TSP-1 production.

Topics: Adult; Androstadienes; Apoptosis; Blotting, Western; Carcinoma, Renal Cell; Cell Line; Chromones; Down-Regulation; Endothelial Cells; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Microscopy, Confocal; Morpholines; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Proto-Oncogene Proteins c-akt; Sirolimus; Thrombospondin 1; Transfection; Tumor Cells, Cultured; Wortmannin

A 19-year old patient with tuberous sclerosis presented with a renal angiomyolipoma. Because animal trials of tuberous sclerosis showed an effect of rapamycin on renal tumors, our patient was administered rapamycin for 6 months. During this time, the renal angiomyolipoma shrank significantly, regrew during an 8-month period, and decreased in size again after readministration of rapamycin.

Topics: Adult; Angiomyolipoma; Antibiotics, Antineoplastic; Humans; Kidney Neoplasms; Male; Sirolimus; Treatment Outcome; Tuberous Sclerosis

CCI-779 (temsirolimus), an ester of rapamycin and an inhibitor of the mammalian target of rapamycin (mTOR), is currently in phase II trials for treatment of patients with solid cancers. The mTOR functions as a checkpoint for cell proliferation, with upstream Akt and downstream p70S6K serving as its most important mediators. The aim of this study was to evaluate the expression and activation of the Akt-mTOR-p70S6K pathway in renal cell carcinoma (RCC), seeking to strengthen the rationale for targeted therapy of RCC using rapamycin or a rapamycin analogue. Tissue microarray sections containing 128 primary RCCs, 22 metastatic RCCs, and 24 non-neoplastic (normal) kidneys (NK) were immunostained with monoclonal antibodies to phosphorylated (p)-Akt (Ser473), p-mTOR (Ser2448), and p-p70S6K (Thr389). Western blotting was performed on 3 cases of clear cell RCC (CRCC) and the corresponding non-neoplastic (normal) renal tissues using the same antibodies. The immunostain scoring system included: (a) location; (b) distribution; and (c) intensity. The normal kidneys provided baseline scores for comparison. Expression of p-Akt, p-mTOR, and p-p70S6K was seen in 100% (n = 24) of NKs and nearly 100% (n = 150) of both primary and metastatic RCCs. The p-p70S6K was located in the nucleus in both NKs and RCCs. The p-Akt was observed in the nucleus and cytoplasm of NKs and in the nucleus and cytoplasm/ membrane (plasmalemma) of RCCs. The p-mTOR was identified in the membrane of NKs and the membrane/nucleus of RCCs. The levels of expression of p-p70S6K, p-mTOR, and p-Akt were significantly higher in RCC than in NK in the overall pattern (intensity and distribution, p <0.05). Western blotting also showed higher expression of p-p70S6K, p-mTOR, and p-Akt in RCCs compared to the corresponding normal kidney tissues (p <0.05). These findings indicate that correlative over-expression and activation of p-Akt, p-mTOR, and p-p70S6K are commonly observed in RCCs. After considering these findings in the context of other established protein circuitries and pathways in RCC, we propose therapeutic approaches that incorporate rapamycin-like agents and other small molecule inhibitors in a combinatorial fashion in future clinical trials for RCC.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Immunohistochemistry; Kidney Neoplasms; Protein Array Analysis; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation

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

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

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

Deregulated phosphatidylinositol 3-kinase (PI3K) signaling pathway is widely implicated in tumor growth and resistance to chemotherapy. While a strong rationale exists for pharmacological targeting of PI3K, only a few proof-of-principle in vivo efficacy studies are currently available. PWT-458, pegylated-17-hydroxywortmannin, is a novel and highly potent inhibitor of PI3K in animal models. Upon in vivo cleavage of its poly(ethyleneglycol) (PEG), PWT-458 releases its active moiety 17-hydroxywortmannin (17-HWT), the most potent inhibitor in its class. Here we show that a single intravenous injection of PWT-458 rapidly inhibited PI3K signaling, as measured by a complete loss of AKT (Ser-473) phosphorylation in xenograft tumors grown in nude mice. Following a daily X5 dosing regimen, PWT-458 demonstrated single-agent antitumor activity in nude mouse xenograft models of U87MG glioma, nonsmall cell lung cancer (NSCLC) A549, and renal cell carcinoma (RCC) A498. Efficacious doses ranged from 0.5 mg/kg to 10 mg/kg, achieving a superior therapeutic index over 17-HWT. PWT-458 augmented anticancer efficacy of a suboptimal dose of paclitaxel against A549 and U87MG tumors. Combination treatment of PWT-458 and an mTOR inhibitor, Pegylated-Rapamycin (Peg-Rapa), resulted in an enhanced antitumor efficacy in U87MG. Finally, PWT-458 in combination with interferon-alpha (Intron-A) caused a dramatic regression of RCC A498, which was not achieved by either agent alone. These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy.

Topics: Androstadienes; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Glioma; Humans; Interferon-alpha; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Nude; Molecular Structure; Molecular Weight; Neoplasm Transplantation; Neoplasms; Paclitaxel; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; Transplantation, Heterologous; Xenograft Model Antitumor Assays

Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFalpha) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel-Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHL-dependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated post-transcriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line; Cell Line, Tumor; Drug Synergism; ErbB Receptors; Gefitinib; Humans; Kidney Neoplasms; Mutation; Protein Kinases; Quinazolines; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein

Functional inactivation of tuberous sclerosis 2 gene (Tsc2) leads to renal carcinogenesis in the hereditary renal carcinoma Eker rat models. Recent studies revealed a role of tuberin, a TSC2 product, in suppressing the p70 S6 kinase (p70S6K) activity via inhibition of mammalian target of rapamycin (mTOR). Phosphorylated S6 protein, a substrate of p70S6K, was expressed in the early lesions in Eker rats, and this expression was suppressed by the treatment of rapamycin, an inhibitor of mTOR. We previously isolated the novel gene Niban expressed in renal carcinogenesis of Eker rats. In this study, we demonstrated that the expression of Niban was detected from early preneoplastic lesions in Eker rats. Interestingly, in contrast to the phosphorylated S6 protein, the expression of Niban was unchanged and early lesions still remained even after treatment with rapamycin. These results might suggest the existence of another pathway independent of mTOR-S6K pathway in Tsc2 mutant renal carcinogenesis. In addition, Niban was also expressed in other renal carcinoma models, including Tsc1 and Tsc2 knockout mice, and various types of human renal cell carcinomas. Thus, Niban was commonly expressed in renal carcinomas and might be a new marker for renal carcinogenesis.

Topics: Amino Acid Sequence; Animals; Biomarkers, Tumor; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kidney Neoplasms; Mice; Molecular Sequence Data; Phosphorylation; Precancerous Conditions; Rats; Repressor Proteins; Ribosomal Protein S6 Kinases; Sirolimus; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

The emerging anti-cancer approach is based on combining a 'traditional' cytotoxic drug with a 'signaling' blocking agent. Such combination, if designed and applied properly, may increase selectivity towards tumor cells. The use of such combinations requires smart planning and choice of the drugs to be combined, their proper dosing as well as correct sequence and schedule of application. The combination of the anti-metabolite gemcitabine and the mTOR blocker, rapamycin, has achieved an impressive response in a patient with metastatic leiomyosarcoma.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Diabetic Nephropathies; Gemcitabine; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Leiomyosarcoma; Liver Neoplasms; Male; Middle Aged; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

Rapamycin is an effective inhibitor of human renal cancer metastasis.. Human renal cell cancer (RCC) is common and is 10 to 100 times more frequent in patients with end-stage renal disease (ESRD) and candidates for renal transplantation. Treatment of metastatic RCC is largely ineffective and is further undermined by immunosuppressive therapy in transplant recipients. A treatment regimen that prevents transplant rejection while constraining RCC progression would be of high value.. We developed a human RCC pulmonary metastasis model using human RCC 786-O as the tumor challenge and the severe combined immunodeficient (SCID) beige mouse as the host. We explored the effect of rapamycin, cyclosporine, or rapamycin plus cyclosporine on the development of pulmonary metastases and survival. The effects of the drugs on tumor cell growth, apoptosis, and expression of vascular endothelial growth factor (VEGF-A) and transforming growth factor beta1 (TGF-beta1) were also investigated.. Rapamycin reduced, whereas cyclosporine increased, the number of pulmonary metastases. Rapamycin was effective in cyclosporine-treated mice, and rapamycin or rapamycin plus cyclosporine prolonged survival. Rapamycin growth arrested RCC 786-O at the G1 phase and reduced VEGF-A expression. Immunostaining of lung tissues for von Willebrand factor was minimal and circulating levels of VEGF-A and TGF-beta1 were lower in the rapamycin-treated mice compared to untreated or cyclosporine-treated mice.. Our findings support the idea that rapamycin may be of value for patients with RCC and that its antitumor efficacy is realized by cell cycle arrest and targeted reduction of VEGF-A and TGF-beta1. A regimen of rapamycin and cyclosporine, demonstrated to be effective in reducing acute rejection of renal allografts, may prevent RCC progression as well, and has the potential to prevent mortality due to RCC in patients with ESRD who have received renal allografts.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Cycle; Cell Line, Tumor; Cyclosporine; Gene Expression; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, SCID; Sirolimus; Survival Rate; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Mutations that inactivate either TSC1 or TSC2 cause tuberous sclerosis. We have used immunoblotting and immunohistochemical analysis to see whether there is phosphorylation of p70 S6 kinase, and the ribosomal S6 protein in angiomyolipomas occurring in tuberous scierosis. Hamartin (encoded by TSC1) and S6K was expressed in all samples. Tuberin (TSC2) was weak or absent in angiomyolipomas, but present in healthy kidney, whereas, phosphorylated p70 S6 kinase and p56 were present only in angiomyolipomas. Our results indicate activation of a mammalian target of rapamycin metabolic pathway in tuberous sclerosis lesions, which contributes to their growth. We suggest that treatment with rapamycin and its analogues could benefit such patients.

Topics: Angiomyolipoma; Animals; Antibiotics, Antineoplastic; Cell Division; Germ-Line Mutation; Humans; Immunoenzyme Techniques; Kidney; Kidney Neoplasms; Mice; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Proteins; Repressor Proteins; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

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

Topics: Graft Rejection; Hemofiltration; Humans; Kidney Diseases; Kidney Neoplasms; Kidney Transplantation; Opportunistic Infections; Renal Dialysis; Sirolimus; Tissue Donors; Tissue Engineering; Urinary Tract Infections

Disruption of the TSC1 or TSC2 gene leads to the development of tumors in multiple organs, most commonly affecting the kidney, brain, lung, and heart. Recent genetic and biochemical studies have identified a role for the tuberous sclerosis gene products in phosphoinositide 3-kinase signaling. On growth factor stimulation, tuberin, the TSC2 protein, is phosphorylated by Akt, thereby releasing its inhibitory effects on p70S6K. Here we demonstrate that primary tumors from tuberous sclerosis complex (TSC) patients and the Eker rat model of TSC expressed elevated levels of phosphorylated mammalian target of rapamycin (mTOR) and its effectors: p70S6K, S6 ribosomal protein, 4E-BP1, and eIF4G. In the Eker rat, short-term inhibition of mTOR by rapamycin was associated with a significant tumor response, including induction of apoptosis and reduction in cell proliferation. Surprisingly, these changes were not accompanied by significant alteration in cyclin D1 and p27 levels. Our data provide in vivo evidence that the mTOR pathway is aberrantly activated in TSC renal pathology and that treatment with rapamycin appears effective in the preclinical setting.

Topics: Animals; Antibiotics, Antineoplastic; Germ-Line Mutation; Kidney Neoplasms; Male; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Rats; Rats, Inbred F344; Repressor Proteins; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Malignancy is a dreaded complication of organ transplantation. Immunosuppressive drug therapy-induced impairment of the organ graft recipient's immune surveillance is considered to be the mechanism for the heightened incidence and metastatic progression. We identified a cell-autonomous and host-immunity independent mechanism for cyclosporine-associated tumor progression. In this study, we investigated the effect of rapamycin on tumor progression, in the presence and absence of cyclosporine.. A spontaneously arising renal adenocarcinoma (renal cancer) of BALB/c origin was used as the model tumor. The effect of rapamycin on renal cancer cell phenotype, molecules (E-cadherin, p27 kip1, cyclin D1) implicated in tumor progression, and the effect of rapamycin on in vivo tumor progression were explored in BALB/c mice and in T-cell, B-cell, and natural killer (NK) cell-deficient severe combined immune deficiency (SCID)-beige mice. In the SCID-beige mice, T24 human bladder transitional cell carcinoma also was used as the tumor inoculum.. Rapamycin conditioning of renal cancer cells upregulated E-cadherin expression and induced phenotypic transition from invasive spindle, or dome-shaped cells, with exploratory pseudopodia to noninvasive cuboidal cells that formed cell-to-cell adhesions. Rapamycin increased p27 kip1, reduced cyclinD1, and arrested the growth of renal cancer cells in G1/S phase. In vivo, rapamycin prevented tumor growth and metastatic progression in syngeneic BALB/c or SCID-beige mice, and in BALB/c or SCID-beige mice treated with cyclosporine. Rapamycin treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells.. Our findings, in addition to unlinking mechanisms of immunosuppression from that of tumor progression, suggest that rapamycin may be of value for the management of posttransplant malignancy.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; B-Lymphocytes; Cadherins; Carcinoma, Renal Cell; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; DNA Primers; Genes, Tumor Suppressor; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Neoplasms; Killer Cells, Natural; Mice; Mice, Inbred BALB C; Mice, SCID; Sirolimus; T-Lymphocytes; Tacrolimus; Tumor Cells, Cultured; Tumor Suppressor Proteins