sirolimus and Neoplasm-Metastasis

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; 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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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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

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

We evaluated if standard hormonal therapy (HT) could be improved by the addition of mammalian target of rapamycin inhibitors (mTOR-I) in metastatic luminal breast cancer. A meta-analysis on 4 phase II-III randomized clinical trials was performed. Pooled hazard ratio (HR) for progression free survival (PFS)/ time to progression (TTP) was 0.62 in favor of mTOR-I+HT arm (95% confidence interval [CI] 0.55-0.70; p<0.0001). There was significant heterogeneity for PFS/TTP (Cochran's Q 32, p<0.0001, I2 index 90.6%). Pooled HR for overall survival (OS) was 0.84 in favor of the combination arm (95% CI 0.71-0.99; p=0.04). Heterogeneity was not significant (Cochran's Q 4.47, p=0.1, I2 index 55.3%). Pooled risk ratio (RR) for objective response rate (ORR) was 0.88 in favor of experimental arm (95% CI 0.85-0.91; p<0.0001). Heterogeneity was not significant (Cochran's Q 2.11, p=0.3, I2 index 5.2%). Adverse events (AEs), in particular those of grade 3-4, mostly occurred in mTOR-I+HT arm. Combination therapy of HT plus mTOR-I improves the outcome of metastatic luminal breast cancer patients. Our results provide evidence of a class-effect of these targeting molecules.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Neoplasm Metastasis; Outcome Assessment, Health Care; Proportional Hazards Models; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Sirolimus; Tamoxifen; TOR Serine-Threonine Kinases

Endocrine therapy is the recommended systemic therapy for hormone receptor (HR) positive metastatic breast cancer (MBC). However so far the limited number of endocrine agents and the onset of endocrine resistance have severely limited the therapeutic options for this patients. In the last years many targeted agents have been investigated to prevent or overcome endocrine resistance; only a few of them have been found effective in HR positive MBC, such as everolimus, CK4/6 inhibitors and HDAC inhibitors. Furthermore, translational medicine studies using next generation sequencing technologies have evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with targeted agents benefit. In some studies predictive biomarkers have been identified and many ongoing studies are evaluating the efficacy of targeted drugs in HR positive MBC patients selected for biomarkers or stratified by pathways amplification.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Female; Humans; Neoplasm Metastasis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Sirolimus; Translational Research, Biomedical; Treatment Outcome

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

Endocrine therapy remains a mainstay in the treatment of hormone-sensitive metastatic breast cancer. Nevertheless, acquired resistance to endocrine therapy is an important clinical problem. Understanding the mechanisms of resistance is fundamental in order to develop new therapeutic strategies such as mTOR inhibition through everolimus. Its efficacy in association with endocrine therapy has been shown in two randomized trials. However, the addition of everolimus to endocrine therapy is accompanied by a significant increase in potentially severe side effects. Identifying and adequately addressing these side effects is crucial to decrease toxicity of these new therapies.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Neoplasm Metastasis; Sirolimus; TOR Serine-Threonine Kinases

Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Humans; Neoplasm Metastasis; Receptor, ErbB-2; Sirolimus

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

Patient outcomes remain poor for advanced or metastatic soft tissue sarcomas (STS) and bone sarcomas despite a growing number of clinical trials involving single- and multi-agent chemotherapy. mTOR is an intracellular kinase that plays a central role in regulating cell growth, metabolism, survival and proliferation. mTOR inhibitors including temsirolimus, everolimus and ridaforolimus have demonstrated broad anticancer activity. Ridaforolimus is a non-prodrug analog of rapamycin (sirolimus) with conserved affinity for mTOR but improved solubility, stability and bioavailability when compared with sirolimus. Early clinical trials reveal a reproducible and predictable pharmacokinetic profile, a potent, rapid and prolonged target inhibition and an acceptable safety and tolerability profile. Phase II and III trials of ridaforolimus have produced promising clinical activity against advanced sarcomas and will be presented.

Topics: Antineoplastic Agents; Bone Neoplasms; Clinical Trials as Topic; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Sarcoma; Sirolimus; Soft Tissue Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

Hepatitis B reactivation can occur with cytotoxic chemotherapy in patients with hepatitis B and cancer. Reactivation can occur in a patient with chronic hepatitis, an inactive carrier, or one with resolved hepatitis. Clinical presentation may range from subclinical elevation of liver enzymes to fatal fulminant hepatic failure. Mammalian target of rapamycin inhibitors, which include everolimus, are a new generation of targeted agents that are currently approved for many cancers (since March 2009) including advanced hormone receptor positive, human epidermal growth factor receptor 2-negative breast cancer, in conjunction with exemestane (as of July 2012). We are therefore still learning the various adverse events that occur with this new class of agents. Here, we present an unfortunate case of fatal hepatitis B reactivation in a woman with metastatic breast cancer treated with everolimus and exemestane. We have detailed the controversies around hepatitis B screening prior to immunosuppressive therapy. Clinicians and patients should be aware of this rare but fatal complication prior to everolimus use, and a detailed history, screening for hepatitis B and prophylactic antiviral treatment should be considered.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease Progression; Everolimus; Fatal Outcome; Female; Hepatitis B; Hepatitis B virus; Humans; Middle Aged; Neoplasm Metastasis; Sirolimus; Treatment Outcome; Virus Activation

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

Gastric cancer remains one of the most common types of cancer worldwide, and most patients present withadvanced disease. Sixty percent of these patients eventually relapse after curative surgical resection, and combinationchemotherapy regimens only provide limited survival benefits. Mammalian target of rapamycin (mTOR) is a new targetof cancer therapies. Preclinical data suggest that the suppression of the mTOR pathway inhibits the progression of gastriccancer in vitro and in animal models. In clinical trials, the mTOR inhibitor, everolimus, was well tolerated in phase I/IIstudies on patients with metastatic gastric cancer. The efficacy of everolimus was promising in a phase II clinical trial, butin a recently published phase III clinical trial everolimus monotherapy do not significantly improve the overall survival ofpatients with advanced gastric cancer who had been previously treated with one or two lines of systemic chemotherapy.Phosphoinositide 3-kinase/mTOR dual inhibitors have not yet entered early-stage clinical trials in patients with advanced gastric cancer. Further studies are needed to establish the role of mTOR inhibitors for the treatment of gastric cancer.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Everolimus; Humans; Neoplasm Metastasis; Sirolimus; Stomach Neoplasms; TOR Serine-Threonine Kinases

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

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

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

Soft-tissue sarcomas (STS) comprise a heterogeneous group of rare malignancies from mesenchymal tissues. Although outcome varies by histology, adults with disseminated metastatic STS have a poor prognosis despite current treatment options. The authors reviewed commonly used clinical end points for STS and discussed which end points may be appropriate for evaluating the clinical benefit of novel targeted therapies. In sarcoma, surrogates for both overall survival, the gold standard end point, and the objective response rate, measured by Response Evaluation Criteria in Solid Tumors, are commonly used. More appropriate end points for evaluating newly targeted agents include progression-free survival and clinical benefit rate. Results from recently completed Phase III trials of two targeted therapies in advanced STS, the mTOR inhibitor ridaforolimus and the multikinase inhibitor pazopanib, should shed light on whether progression-free survival and clinical benefit rate are appropriate end points in advanced STS.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease-Free Survival; Drug Substitution; Drugs, Investigational; Endpoint Determination; Humans; Indazoles; Molecular Targeted Therapy; Neoplasm Metastasis; Outcome and Process Assessment, Health Care; Prognosis; Pyrimidines; Sarcoma; Sirolimus; Sulfonamides; Survival Rate; TOR Serine-Threonine Kinases; Treatment Outcome

Metastatic melanoma is one of the most resistant tumors to standard chemotherapy approaches. The median overall survival of patients diagnosed with metastatic melanoma is lower than 9 months. Current approved treatments offer only marginal survival advantages. New immunotherapeutic targets have appeared recently trying to modulate the host immune response against the tumor. New targeted agents have changed the standard of care of other solid tumor types like breast cancer. Here, we discuss the new advances and achievements in the treatment of this highly resistant disease.

Topics: Adoptive Transfer; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Everolimus; Humans; Immunotherapy; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Sirolimus; Skin Neoplasms

In April 2009, an expert group of 11 physicians and clinical nurses met to discuss the management of selected adverse events associated with the use of everolimus for the treatment of metastatic renal cell carcinoma (mRCC). Everolimus is an orally administered inhibitor of the mammalian target of rapamycin that recently received approval from the European Medicines Agency for the treatment of advanced RCC that has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy, and from the United States Food and Drug Administration for treatment of advanced RCC after failure of sorafenib or sunitinib. Before the approval of everolimus, no standard therapy existed for the treatment of mRCC after failure of VEGF-targeted therapy. RECORD-1 (Renal Cell cancer treatment with Oral RAD001 given Daily) was the pivotal multicenter, phase III, randomised, double-blind, placebo-controlled trial of everolimus that led to approval for patients with disease progression on or after treatment with VEGF-targeted agents. Safety data from RECORD-1 were reviewed by these clinicians, all of whom had experience using everolimus in patients with mRCC. Adverse events discussed were non-infectious pneumonitis, infections, stomatitis and metabolic abnormalities.. The outcome of this discussion is summarised here. Guidance for management of these adverse events is provided. Both clinicians and patients should be aware of the potential side-effects of everolimus and understand that these side-effects are manageable with standard care to optimise patient benefit.

Topics: Aged; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease Progression; Everolimus; Humans; Immunosuppressive Agents; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Placebos; Pneumonia; Randomized Controlled Trials as Topic; Research Design; Risk; Sirolimus; Stomatitis; Time Factors; Treatment Outcome

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

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

Topics: Animals; Antibiotics, Antineoplastic; Biomarkers, Tumor; Cyclooxygenase 2 Inhibitors; Diagnostic Imaging; Humans; Inflammation; Inflammation Mediators; Mice; Molecular Targeted Therapy; Neoplasm Metastasis; Neovascularization, Pathologic; Receptors, CXCR4; 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

Tumor cell migration is a key step in the formation of cancer metastasis. The mammalian target of rapamycin (mTOR), a highly conserved and ubiquitously expressed serinethreonine kinase, has been intensely studied for over a decade as a central regulator of cell growth, proliferation, differentiation, and survival. Recent data have shown that mTOR also plays a critical role in the regulation of tumor cell motility and cancer metastasis. Here, we briefly review recent advances regarding mTOR signaling in tumor cell motility. We also discuss recent findings about the mechanism by which rapamycin, a specific inhibitor of mTOR, inhibits cell motility in vitro and metastasis in vivo.

Topics: Animals; Cause of Death; Cell Line; Cell Movement; Humans; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Ligands; Neoplasm Metastasis; Neoplasms; Protein Serine-Threonine Kinases; Receptor, IGF Type 1; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. The two most common histologic variants are the embryonal and alveolar subtypes. Although successive collaborative group clinical trials have improved survival rates for many RMS patients, the outcome for those patients with metastatic or recurrent disease remains poor. Recent studies have pointed to a possible mesenchymal stem cell as the progenitor for alveolar RMS. Other studies have implicated several cellular mechanisms and pathways being involved in RMS pathogenesis and survival, such as the cyclin-dependent kinase inhibitors, insulin-like growth factor pathway, and the mammalian target of rapamycin pathway, thus providing potential avenues for targeted therapy. Recent clinical trials have tried to improve risk stratification and prediction of clinical outcome based upon clinical or radiographic response to initial therapy and also to determine the role of high-dose chemotherapy with stem cell rescue in high-risk RMS patients.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Disease Progression; Female; Humans; Male; Mesenchymal Stem Cells; Mice; Neoplasm Metastasis; Neoplasm Staging; Neoplastic Stem Cells; Prognosis; Protein Kinase Inhibitors; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Risk Factors; Secondary Prevention; Signal Transduction; Sirolimus; Soft Tissue Neoplasms; Survival Rate; Tomography; TOR Serine-Threonine Kinases

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 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

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

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

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

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 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

Further progress in the therapy of malignant diseases is expected from the introduction of potent antimetastatic drugs. Surveying of the complex and multi-step behavior of the metastatic process, compounds showing inhibitory action against tumor cell migration may be ranked among the promising antimetastatic agents. Our present study indicate, however, that the antimigratory actions of certain antitumor drugs (doxorubicin, taxol), and inhibitors of signal transduction (PD-98059, LY-294002, SB-203580) are highly dependent on the assay applied (Boyden-chamber, 3D ECM cell culture). It has been proposed that agents interrupting cell-extracellular matrix contacts (hexyldeoxyuridine, borrelidin) and others interfering with the regulatory mechanism of gene translation (rapamycin, ribavirin) could be regarded as leading compounds in the antimetastatic drug development process. Nevertheless, for introducing diagnostically based targeted therapy the forthcoming tasks must include the further elucidation of the molecular mechanisms implicated in the amoeboid and cluster type of cell migration.

Topics: Animals; Antineoplastic Agents; Cell Movement; Chromones; Deoxyuridine; Doxorubicin; Enzyme Inhibitors; Fatty Alcohols; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Morpholines; Neoplasm Metastasis; Paclitaxel; Pyridines; Ribavirin; Signal Transduction; Sirolimus

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

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

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

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

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

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; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; 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

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

This European phase IIIb, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2.. Post-menopausal women aged ≥18 years with hormone receptor-positive, human epidermal growth factor-receptor-2-negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors were enrolled. The primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). The secondary objective was to evaluate AEs of grade 3/4 severity.. The median treatment duration was 5.1 months [95% confidence interval (CI) 4.8-5.6] for EVE and 5.3 months (95% CI 4.8-5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXE-related or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported non-hematologic AEs were (overall %, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AEs were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly (≥70 years) versus non-elderly patients (23.8% versus 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related.. This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. Although the patients were more heavily pretreated, the safety profile of EVE plus EXE in BALLET was consistent with BOLERO-2.. EudraCT Number: 2012-000073-23.

Topics: Aged; Aged, 80 and over; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; ErbB Receptors; Everolimus; Female; Humans; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Postmenopause; Receptor, ErbB-2; Receptors, Estrogen; Sirolimus

Everolimus, which inhibits the mammalian target of rapamycin (mTOR), is increasingly used in breast cancer and familiarity with its full range of toxicity is critical for practicing oncologists.. We studied hematologic changes in 31 patients with metastatic breast cancer treated in a phase II clinical trial using everolimus. Complete blood counts were collected at baseline, 2 weeks, 4 weeks, every 4 weeks during treatment, and 1 month after discontinuation. Adverse events were defined using Common Toxicity Criteria version 3. Linear mixed models with fixed effects of time and random intercepts and slopes were used to study trends and comparisons were conducted using paired t tests.. Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). These were predominantly grade 1 or 2 and did not require dose modification. Red blood cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) both decreased significantly over time (P < .0001) starting at 2 weeks with no significant change in mean corpuscular hemoglobin concentration (MCHC) (P = .104). Both MCV and MCH increased 1 month after treatment discontinuation (P values < .0001 and .0003, respectively) indicating reversibility of this effect. Although total leukocyte counts remained largely stable, lymphocyte percentage progressively decreased over time with a trend for increased neutrophils.. In addition to anemia, leukopenia, and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. Familiarity with these hematologic changes is prudent as more patients are treated with this class of drugs.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Erythrocyte Count; Erythrocyte Indices; Estradiol; Everolimus; Female; Fulvestrant; Hematologic Diseases; Humans; Leukocyte Count; Leukopenia; Neoplasm Metastasis; Sirolimus; Thrombocytopenia

Although trastuzumab-containing therapies prolong survival in patients with metastatic breast cancer (MBC), most tumors develop trastuzumab resistance, potentially mediated by aberrant phosphatidylinositide 3-kinase (PI3K)/AKT signaling. Ridaforolimus (a mammalian target of rapamycin [mTOR] inhibitor) may overcome trastuzumab resistance by inhibiting PI3K signaling.. A single-arm, phase IIb trial was conducted to evaluate the efficacy and safety of ridaforolimus-trastuzumab in human epidermal growth factor receptor 2-positive (HER2(+)) trastuzumab-refractory MBC (NCT00736970). Ridaforolimus was administered orally (40 mg daily) for 5 d/wk plus weekly trastuzumab. The primary end point was objective response (OR).. Thirty-four patients were enrolled (91% had received 1 or 2 previous trastuzumab-based therapies, whereas 9% had received 3 previous therapies). The most common reasons for discontinuation were disease progression (62%) and adverse events (AEs; 24%). Three patients died; 1 because of bowel perforation, which was possibly ridaforolimus related. Partial response was observed in 5 patients (15%). Median duration of response was 19.1 weeks (range, 15.9-80.1 weeks). Fourteen patients (41%) achieved stable disease (SD); 7 patients (21%) maintained SD for ≥ 24 weeks. The clinical benefit response (CBR) rate was 34.3%. Median progression-free survival (PFS) and overall survival (OS) were 5.4 months (range, 0-20.3 months; 95% confidence interval [CI], 2.0-7.4) and 17.7 months (range, 0-25.9 months; 95% CI, 8.8-20.8), respectively. PFS rate at 6 months was 37%. The most common treatment-related AEs were stomatitis (59%), diarrhea (27%), and rash (27%).. Ridaforolimus-trastuzumab was well tolerated and demonstrated antitumor activity in trastuzumab-resistant HER2(+) MBC.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Sirolimus; Survival Analysis; Trastuzumab

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

Constitutive activation of the PI3K/Akt/mTOR pathway has been suggested as a mechanism of resistance to trastuzumab therapy. This phase II trial was designed to evaluate the safety and clinical activity of daily oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in combination with trastuzumab in HER2-positive metastatic breast cancer following disease progression on prior trastuzumab therapy. Sirolimus 6 mg oral daily dose was administered with a standard dose and schedule of trastuzumab weekly or every 3 weeks. Pharmacodynamic studies included Western blot analysis of S6K1, phosphoS6K1, and mTOR in peripheral mononuclear cells, circulating tumor cells (CTC), and endothelial cells (CEC). Eleven patients were evaluable for safety; and nine were evaluable for response assessment. Subsequent enrollment was stopped due to slow accrual. Study treatment-related grade 3 toxicity included pneumonitis, myelosuppression (leukopenia/anemia), and dermatologic reactions (mucositis, nail changes and rash), with no grade 4 events. One patient received eight cycles (58 weeks) and achieved a partial response. Five patients treated for a total of 101 weeks (median 12 weeks, range 8-47 weeks) achieved stable disease as best response. Overall response rate was 1/9 (11 %) and clinical benefit rate was 4/9 (44 %). There was no statistically significant correlation between response and post-treatment change in levels of the mTOR pathway biomarkers, CTCs, HER2 CTCs, or CECs. Sirolimus 6 mg administered daily with trastuzumab appears to be well tolerated in patients with metastatic HER2-positive breast cancer following disease progression on prior trastuzumab therapy, with evidence of disease activity. mTOR inhibition may overcome resistance to trastuzumab in some HER2-positive tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Breast Neoplasms; Disease Progression; Female; Humans; Immunohistochemistry; Leukocytes, Mononuclear; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Receptor, ErbB-2; Retreatment; Sirolimus; TOR Serine-Threonine Kinases; Trastuzumab; Treatment Outcome

To evaluate feasible doses of weekly everolimus and irinotecan given with cetuximab for previously treated metastatic colorectal cancer (mCRC).. Adults with mCRC that progressed after 5-fluorouracil or capecitabine-plus-oxaliplatin were treated using a sequential dose escalation scheme. Dosing decisions were based on the probability of experiencing a dose-limiting toxicity (DLT) during the first two 21-day treatment cycles.. Patients received everolimus 30 mg/week plus irinotecan 350 mg/m2 q3w (n=5; dose A1) or everolimus 30 mg/week plus irinotecan 250 mg/m2 q3w (n=14; dose B1). Among patients evaluable for the maximum tolerated dose, two out of four in A1 and one out of eight in B1 experienced four DLTs. The trial was terminated early based on changes in clinical practice and emerging data on everolimus dosing.. The feasible doses of everolimus and irinotecan administered with cetuximab as second-line therapy in mCRC were 30 mg/week and 250 mg/m2, respectively.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Everolimus; Female; Humans; Irinotecan; Male; Middle Aged; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Sirolimus

Our study was designed to evaluate the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US-based population focusing on biomarker correlation.. Patients with advanced upper GI adenocarcinomas who progressed after 1-2 prior regimens received everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), toxicity, overall survival (OS) and biomarker correlatives of the mTOR pathway. Target accrual was 50 patients based on one-sided type I error of 10 % and power of 90 %.. Forty-five patients were evaluable, 21 gastric, 11 esophagus and 13 from the GEJ. The median age was 64 (range 38-73); all patients had an ECOG of 0 or 1; and 18 patients (40 %) had only 1 prior regimen. The most common grade 3-4 adverse events included fatigue (24 %) and thrombocytopenia (22 %). We observed 1 partial response with 39 % of evaluable patients having stable disease. Median OS was 3.4 months (95 % CI 2.7-5.6 months), and PFS was 1.8 months (95 % CI 1.7-2.2 months). There was a strong correlation between ≥2 + IHC staining for p-S6 in tumor samples with better PFS (p < 0.0001) and DCR (p = 0.0001).. Our clinical outcomes were inferior to the Asian studies, which may be explained by disease heterogeneity. However, there was a similar strong correlation between clinical benefit and tumor high pS6. Testing this biomarker in patient samples from the randomized phase III Granite trial may lead to a positive predictive marker.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Esophageal Neoplasms; Esophagogastric Junction; Everolimus; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Sirolimus; Stomach Neoplasms

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

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

This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.. Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.. Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.. While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Monitoring; Early Termination of Clinical Trials; Everolimus; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Protein Kinase Inhibitors; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases

Pancreatic adenocarcinomas are associated with a poor survival prognosis. Besides curative surgical resection, only limited therapies with modest impact are available. New evidence suggests that the mammalian target of rapamycin pathway may be involved in the pathogenesis of neuroendocrine tumors, and breast and renal cell cancer. The phase I study described here was therefore designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of the mammalian target of rapamycin inhibitor everolimus in combination with gemcitabine in patients with advanced pancreatic cancer. Eligible patients had histologically confirmed locally advanced and/or metastatic pancreatic carcinoma and were administered 5 mg everolimus every second day (cohort 1, 2, 3) or 5 mg daily (cohort 4, 5) in combination with escalating low-dose gemcitabine. It was found that if two patients showed DLTs, MTD was reached and gemcitabine dose escalation was stopped at this level. Twenty-seven patients were enrolled in the study (cohort 1: n=3; cohort 2: n=4; cohort 3: n=6; cohort 4: n=7; cohort 5: n=7) and received a maximum 600 mg gemcitabine/week. In cohort 5, two of the six patients experienced DLTs (grade 3 liver toxicity lasting for>7 days). MTD was measured as 400 mg/m/week gemcitabine plus 5 mg/day everolimus. The MTD of a low-dose gemcitabine treatment in combination with everolimus was determined and no new safety concerns were identified in patients with advanced pancreatic cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Everolimus; Female; Gemcitabine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neovascularization, Pathologic; Pancreas; Pancreatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

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

Platinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN.. Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m(2) and then 250 mg/m(2) weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2.. The study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival.. The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Cetuximab; Disease-Free Survival; Drug Administration Schedule; Everolimus; Female; Head and Neck Neoplasms; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Recurrence; Sirolimus; Squamous Cell Carcinoma of Head and Neck

The phosphatidylinositol-3 kinase/serine-threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor ridaforolimus were evaluated in this study.. This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40mg for 5 consecutive days followed by a 2day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting.. 31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9 and 26.5months. An additional 18 patients showed disease stabilization (52.9%) for a median duration of 6.6months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status.. Oral ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Endometrioid; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

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

The aim of this study was to examine the efficacy and safety of everolimus in patients with progressive unresectable adenoid cystic carcinoma (ACC).. Histologically confirmed ACC patients with documented disease progression within 12 months prior to the study entry were eligible. Everolimus was given at a dose of 10 mg daily until progression or occurrence of unacceptable toxicities. The primary endpoint was a 4-month progression-free survival (PFS).. A total of 34 patients were enrolled. The 4-month PFS probability was 65.5% (95% one-sided confidence interval [CI], 47.7 to infinity). Median PFS duration was 11.2 months (95% CI, 3.6 to 15.8). Complete or partial response was not achieved. Twenty-seven (79.4%, 95% CI, 63.2 to 89.6) patients showed stable disease (SD). Tumor shrinkage within SD criteria was observed in 15 patients (44.1%) and SD lasting 6 months was observed in 13 patients (38.2%). Four patients had disease progression. Among the 18 patients with both pre- and post-treatment (at 8 weeks) FDG-PET scans available, 8 patients (44.4%) showed a partial metabolic response, defined as a ≥25% reduction in maximum standardized uptake values (SUVmax). The most common adverse events were stomatitis, anemia, asthenia, and leukopenia. No unexpected everolimus related toxicities were reported.. Everolimus showed promising efficacy and good tolerability in progressive unresectable ACC.. ClinicalTrials.gov identifier, NCT01152840.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Adenoid Cystic; Everolimus; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Positron-Emission Tomography; Sirolimus; Treatment Outcome; Tumor Burden

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

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

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

Recent data indicate that there is a significant cross-talk between the PI3K/Akt/mTOR and androgen receptor signaling pathways. We evaluated safety and tolerability as well as potential drug-drug interaction of ridaforolimus, a mammalian target of rapamycin (mTOR) inhibitor, when combined with the androgen receptor inhibitor bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer.. Patients were treated with the combination of ridaforolimus 30 mg/day for 5 consecutive days each week and bicalutamide 50 mg/day. Ridaforolimus pharmacokinetics was assessed with and without bicalutamide.. Twelve patients were enrolled including 1 screen failure. Dose reductions were required in 7 patients. Three of the 11 patients experienced a dose-limited toxicity, 1 with Grade 3 hyperglycemia and 2 with Grade 2 stomatitis leading to <75 % of planned ridaforolimus dose during the first 35 days of study treatment. The pharmacokinetic results showed no differences in exposures to ridaforolimus with and without concomitant bicalutamide administration.. Although there was no evidence of a clinically relevant pharmacological drug-drug interaction, the occurrence of dose-limiting toxicities in 3 of 11 evaluable patients at a reduced dose of ridaforolimus of 30 mg/day suggests that this combination may not be well suited for asymptomatic or minimally symptomatic prostate cancer patients.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Interactions; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Nitriles; Orchiectomy; Prospective Studies; Prostatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Tosyl Compounds

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

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

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

Postmenopausal women with hormone receptor-positive (HR(+)) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR(+) advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest.. BOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR(+) advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up.. Baseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths.. Adding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR(+) advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population.

Topics: Aged; Aged, 80 and over; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Follow-Up Studies; Humans; International Agencies; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Safety; Sirolimus; Survival Rate

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

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

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

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

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

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

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

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

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

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

This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy.. Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control.. Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD.. Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Transitional Cell; Everolimus; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Sirolimus; Urinary Bladder Neoplasms

Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs).. This open-label, phase II study randomly assigned postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned.. The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%).. This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Everolimus; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Sirolimus; Tamoxifen

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

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

Despite advances in the the first- and second-line treatment of metastatic breast cancer, there remains a large unmet need for additional treatment options. As preclinical studies have suggested that combining everolimus with carboplatin may produce higher activity than each drug by itself, we initiated a phase I study of this combination.. Patients with pre-treated metastatic breast cancer received weekly carboplatin at AUC2 and daily oral everolimus at different dose-levels (level I: 2.5 mg; II: 5 mg; III: 7.5 mg; IV: 10 mg). Three patients were assigned to dose-levels I to III, and six to dose-level IV. The primary end-point was to determine the maximum tolerated dose (MTD).. Fifteen patients were recruited to the study. The median number of previous chemotherapies was four (range: 1-11). No dose-limiting toxicity occurred at levels I-III during the first cycle. Based on the pre-determined definition, the maximum planned dose-level IV was selected as the MTD. Patients received a median of four cycles of treatment (range 1-13). Most frequent grade 3 and 4 toxicities included leukopenia, thrombocytopenia and infection. Response rates were as follows: 21% partial response, 43% stable disease, and 36% progressive disease.. Carboplatin and everolimus is a well-tolerated combination for heavily pre-treated metastatic breast cancer. Everolimus (10 mg/d) and carboplatin (AUC2 weekly) were defined as the MTD. This dose is currently being employed in an ongoing phase II trial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Everolimus; Female; Humans; Middle Aged; Neoplasm Metastasis; Sirolimus; TOR Serine-Threonine Kinases

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

To determine the feasible dose and schedule for everolimus, an oral mTOR inhibitor, combined with vinorelbine and trastuzumab for patients with HER2-overexpressing metastatic breast cancer pretreated with trastuzumab. In this phase Ib multicenter, Bayesian dose-escalation study, 50 patients received everolimus 5 mg/day, 20 mg/week, or 30 mg/week plus vinorelbine (25 mg/m² on day 1 and 8 every 3 weeks) and trastuzumab (2 mg/kg weekly). Endpoints included end-of-cycle-1 dose-limiting toxicity (DLT) rate (primary endpoint), safety, relative dose intensity, overall response rate (ORR), and pharmacokinetics. Grade 3/4 neutropenia was the most common end-of-cycle-1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg/day and 30 mg/week cohorts, respectively. Other end-of-cycle-1 DLTs included single cases of febrile neutropenia, grade 3 stomatitis with concomitant fatigue, grade 2 stomatitis, grade 3 anorexia, and grade 2 acneiform dermatitis, all in the 5-mg/day cohort. Based on the recorded DLTs and global safety, everolimus 5 mg/day and 30 mg/week were chosen as the optimal dose levels for the daily and weekly arms. Forty-seven patients were evaluable for efficacy. ORR was 19.1%, with a disease control rate of 83.0% and median progression-free survival of 30.7 weeks. No drug interaction was observed between everolimus and vinorelbine. Everolimus combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with HER2-overexpressing metastatic breast cancer that progressed on trastuzumab (NCT00426530).

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Drug Administration Schedule; Everolimus; Female; Genes, erbB-2; Humans; Middle Aged; Neoplasm Metastasis; Prognosis; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Trastuzumab; Treatment Outcome; Vinblastine; Vinorelbine

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

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

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

Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy.. This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus.. Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss.. Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Disease-Free Survival; Everolimus; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; PTEN Phosphohydrolase; Receptor, ErbB-2; Salvage Therapy; Sirolimus; TOR Serine-Threonine Kinases; Trastuzumab

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

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

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

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

In this phase 2 study, the activity and tolerability of the combination of bevacizumab, an inhibitor of angiogenesis, and everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), was evaluated in the treatment of patients with metastatic melanoma.. Patients with metastatic melanoma who had received up to 2 previous systemic regimens (chemotherapy and/or immunotherapy) were eligible. Previous treatment with angiogenesis or mTOR inhibitors was not allowed. All patients received bevacizumab at a dose of 15 mg/kg intravenously every 21 days and everolimus at a dose of 10 mg orally daily. Patients were re-evaluated every 6 weeks; those with an objective response or stable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST]) continued therapy until tumor progression or unacceptable toxicity occurred.. Fifty-seven patients with metastatic melanoma received a median of 4 treatment cycles (range, 1-14+ cycles). Seven patients (12%) achieved major responses, whereas 33 patients (58%) were found to have stable disease at the time of first evaluation. The median progression-free and overall survivals were 4 months and 8.6 months, respectively. Approximately 43% of patients were alive after 12 months of follow-up. The treatment regimen was well tolerated by the majority of patients.. The combination of bevacizumab and everolimus was found to have moderate activity and was well tolerated in the treatment of patients with metastatic melanoma. Further exploration of agents with these mechanisms of action is indicated, perhaps in combination with inhibitors of the mitogen-activated protein kinase (MAPK) pathway.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Everolimus; Female; Humans; Male; Melanoma; Middle Aged; 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. 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

Tumor cell-intrinsic programmed death-ligand 1 (PD-L1) signals mediate immunopathologic effects in breast, colon, and ovarian cancers and in melanomas, but bladder cancer (BC) effects are unreported. We show here that BC cell-intrinsic PD-L1 signals in mouse MB49 and human RT4, UM-UC3, and UM-UC-14 BC cells regulate important pathologic pathways and processes, including effects not reported in other cancers. α-PD-L1 antibodies reduced BC cell proliferation in vitro, demonstrating direct signaling effects. BC cell-intrinsic PD-L1 promoted mammalian target of rapamycin complex 1 (mTORC1) signals in vitro and augmented in vivo immune-independent cell growth and metastatic cancer spread, similar to effects we reported in melanoma and ovarian cancer. BC cell-intrinsic PD-L1 signals also promoted basal and stress-induced autophagy, whereas these signals inhibited autophagy in melanoma and ovarian cancer cells. BC cell-intrinsic PD-L1 also mediated chemotherapy resistance to the commonly used BC chemotherapy agents cis-platinum and gemcitabine and to the mTORC1 inhibitor, rapamycin. Thus, BC cell-intrinsic PD-L1 signals regulate important virulence and treatment resistance pathways that suggest novel, actionable treatment targets meriting additional studies. As a proof-of-concept, we showed that the autophagy inhibitor chloroquine improved cis-platinum treatment efficacy in vivo, with greater efficacy in PD-L1 null versus PD-L1-replete BC.

Topics: Animals; Antibiotics, Antineoplastic; Autophagy; B7-H1 Antigen; Cell Line, Tumor; Cell Proliferation; Chloroquine; Cisplatin; Deoxycytidine; Drug Resistance, Neoplasm; Female; Gemcitabine; Gene Expression; Humans; Mechanistic Target of Rapamycin Complex 1; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Ovarian Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Sirolimus; Urinary Bladder Neoplasms

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

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

The aim of this study was to analyze the effects of rapamycin treatment on apoptosis via mTOR pathway in metastatic and non-metastatic human breast cancer cell lines by immunohistochemical and TUNEL analysis.. MCF-7 and MDA-MB 231 cell lines were incubated under standard conditions forming Rapamycin and control groups. In immunohistochemical evaluation; mTOR pathway was evaluated with anti-IGF1, anti-PI3K, anti-pAKT1/2/3, anti-mTORC1, anti-mTORC2 and anti-ERK1 antibodies. The effect of apoptosis was also confirmed by TUNEL method.. In this study, activation of PI3K/AKT/mTOR and related molecular pathways in the MDA-MB 231 and MCF-7 breast cancer cell line was evaluated and it was observed that these pathways could play a key role in cancer development. Increased apoptotic cells were observed in mTORC1 inhibition by Rapamycin administration.. Targeting the mTOR pathway in breast cancer treatment may be a treatment option. In addition, the demonstration and confirmation of increased apoptosis in Rapamycin treated groups suggested that Rapamycin, an inhibitor of mTOR, is promising in the treatment of breast cancer (Tab. 2, Fig. 3, Ref. 66).

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Humans; MCF-7 Cells; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases

Preclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy.. Cohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle.. Nine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3-4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected.. The combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.

Topics: Adult; Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Pancreatic Ductal; Drug Therapy, Combination; Female; Hedgehog Proteins; Humans; Immunosuppressive Agents; Male; Maximum Tolerated Dose; Middle Aged; Negative Results; Neoplasm Metastasis; Pancreatic Neoplasms; Pyridines; RNA, Neoplasm; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

SOCS5 is a member of the suppressor of cytokine signaling (SOCS) protein family with important yet incompletely understood biological functions in cancer. In hepatocellular carcinoma (HCC), controversial tumor-promoting and tumor-suppressive roles of SOCS5 have been reported. Our study aims to unravel novel functions of SOCS5 in HCC, especially that affecting metastasis. We examined the expression levels of SOCS5 in HCC using publicly available datasets, and in our patient cohort, using quantitative real-time PCR, western blotting, and immunohistochemistry. The association of SOCS5 expression with clinical pathological data of HCC patients was examined and that with the mTOR pathway was predicted. We further studied the effects of SOCS5 on PI3K/Akt/mTOR activity; HCC cell autophagy, migration, and invasion; and HCC cell metastasis in vitro and in vivo. We observed that SOCS5 was significantly overexpressed in HCC tissues, compared to adjacent non-tumor liver tissues, in both the public datasets and in our patient cohort. SOCS5 overexpression was significantly and inversely correlated with HCC patient prognosis. Moreover, SOCS5 overexpression promoted HCC cell migration and invasion in vitro by inactivating PI3K/Akt/mTOR-mediated autophagy. Conversely, SOCS5 inhibition suppressed HCC cell migration and invasion in vitro by activating PI3K/Akt/mTOR-mediated autophagy. Dual inhibition of SOCS5 and mTOR further enhanced autophagy and the subsequent anti-metastatic effects on HCC cells. In vivo, stable knockdown of SOCS5 reduced HCC cell metastasis. Overall, our study revealed a novel metastasis-promoting function of SOCS5 in HCC, acting via the PI3K/Akt/mTOR-mediated autophagy pathway. Combined inhibition of SOCS5 and mTOR may be a potential therapeutic approach to inhibit HCC metastasis and prolong patient survival.

Topics: Animals; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Dimethyl Sulfoxide; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Models, Biological; Multivariate Analysis; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Prognosis; Proto-Oncogene Proteins c-akt; RNA, Messenger; Sirolimus; Suppressor of Cytokine Signaling Proteins; TOR Serine-Threonine Kinases

Tumor microenvironments expose cancer cells to heterogeneous, dynamic environments by shifting availability of nutrients, growth factors, and metabolites. Cells integrate various inputs to generate cellular memory that determines trajectories of subsequent phenotypes. Here we report that short-term exposure of triple-negative breast cancer cells to growth factors or targeted inhibitors regulates subsequent tumor initiation. Using breast cancer cells with different driver mutations, we conditioned cells lines with various stimuli for 4 hours before implanting these cells as tumor xenografts and quantifying tumor progression by means of bioluminescence imaging. In the orthotopic model, conditioning a low number of cancer cells with fetal bovine serum led to enhancement of tumor-initiating potential, tumor volume, and liver metastases. Epidermal growth factor and the mTORC1 inhibitor ridaforolimus produced similar but relatively reduced effects on tumorigenic potential. These data show that a short-term stimulus increases tumorigenic phenotypes based on cellular memory. Conditioning regimens failed to alter proliferation or adhesion of cancer cells in vitro or kinase signaling through Akt and ERK measured by multiphoton microscopy in vivo, suggesting that other mechanisms enhanced tumorigenesis. Given the dynamic nature of the tumor environment and time-varying concentrations of small-molecule drugs, this work highlights how variable conditions in tumor environments shape tumor formation, metastasis, and response to therapy.

Topics: Animals; Carcinogenesis; Cell Adhesion; Cell Count; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Disease Progression; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Luminescent Measurements; Mechanistic Target of Rapamycin Complex 1; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Serum Albumin, Bovine; Sirolimus; Triple Negative Breast Neoplasms; Tumor Microenvironment

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

Therapeutic strategies targeting both cancer cells and associated cells in the tumor microenvironment offer significant promise in cancer therapy. We previously reported that generation 5 (G5) dendrimers conjugated with cyclic-RGD peptides target cells expressing integrin alpha V beta 3. In this study, we report a novel dendrimer conjugate modified to deliver the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In vitro analyses demonstrated that this drug conjugate, G5-FI-RGD-rapamycin, binds to prostate cancer (PCa) cells and fibroblasts to inhibit mTOR signaling and VEGF expression. In addition, G5-FI-RGD-rapamycin inhibits mTOR signaling in cancer cells more efficiently under proinflammatory conditions compared to free rapamycin. In vivo studies established that G5-FI-RGD-rapamycin significantly inhibits fibroblast-mediated PCa progression and metastasis. Thus, our results suggest the potential of new rapamycin-conjugated multifunctional nanoparticles for PCa therapy.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Dendrimers; Fibroblasts; Flow Cytometry; Humans; Integrin alphaVbeta3; Male; Mice; Neoplasm Metastasis; PC-3 Cells; Peptides, Cyclic; Prostatic Neoplasms; Sirolimus

The outcome of patients who progress on front-line immune-based combination regimens (IC) including immune checkpoint inhibitors (CPI) and receive subsequent systemic therapy is unknown.. Retrospective analysis of consecutive patients with clear-cell mRCC who progressed on one of seven clinical trials investigating an IC and received ≥1 line of subsequent VEGFR TKI therapy.. Thirty-three patients [median age 57 (37-77), 85% male, 73% ECOG 0] were included. For evaluable patients (N = 28), the best response to first subsequent therapy was 29% partial response, 54% stable disease, and 18% progressive disease. The median PFS (mPFS) for first subsequent therapy was 6.4 months (95% CI, 4.4-8.4); no difference in mPFS by prior type of IC (VEGFR TKI-CPI vs. CPI-CPI) was noted (p = 0.310). Significant AEs were observed in 30% of patients, more frequently transaminitis (9%).. VEGFR TKIs have clinical activity in mRCC refractory to IC therapy, possibly impacted by the mechanism of prior combination therapy.

Topics: Adult; Aged; Carcinoma, Renal Cell; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Everolimus; Female; Humans; Immunotherapy; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Sirolimus; Vascular Endothelial Growth Factor Receptor-1

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Pan-genomic analyses identified p53/Rb and WNT/β-catenin signaling pathways as main contributors to the disease. However, isolated β-catenin constitutive activation failed to induce malignant progression in mouse adrenocortical tumors. Therefore, there still was a need for a relevant animal model to study ACC pathogenesis and to test new therapeutic approaches. Here, we have developed a transgenic mice model with adrenocortical specific expression of SV40 large T-antigen (AdTAg mice), to test the oncogenic potential of p53/Rb inhibition in the adrenal gland. All AdTAg mice develop large adrenal carcinomas that eventually metastasize to the liver and lungs, resulting in decreased overall survival. Consistent with ACC in patients, adrenal tumors in AdTAg mice autonomously produce large amounts of glucocorticoids and spontaneously activate WNT/β-catenin signaling pathway during malignant progression. We show that this activation is associated with downregulation of secreted frizzled related proteins (Sfrp) and Znrf3 that act as inhibitors of the WNT signaling. We also show that mTORC1 pathway activation is an early event during neoplasia expansion and further demonstrate that mTORC1 pathway is activated in ACC patients. Preclinical inhibition of mTORC1 activity induces a marked reduction in tumor size, associated with induction of apoptosis and inhibition of proliferation that results in normalization of corticosterone plasma levels in AdTAg mice. Altogether, these data establish AdTAg mice as the first preclinical model for metastatic ACC.

Topics: Adrenocortical Carcinoma; Animals; Antigens, Polyomavirus Transforming; beta Catenin; Humans; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Transgenic; Multiprotein Complexes; Neoplasm Metastasis; Retinoblastoma Protein; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53; Wnt Signaling Pathway

Perivascular epithelioid cell tumors (PEComas) are very rare mesenchymal tumors, characterized by the presence of perivascular epithelioid cells. Despite their often benign nature, malignant variants with a locally aggressive growth pattern and even distant metastases are known. We describe two cases of malignant PEComas. The first patient had an extensive peritoneal spread and a history of multiple resections, and received the mechanistic target of rapamycin inhibitor sirolimus in a postoperative setting as maintenance therapy. The second patient presented with locally advanced disease in the iliac fossa and was treated with sirolimus in a neoadjuvant setting and achieved complete remission. Both patients have been under treatment for 18 and 52 months, respectively, and are currently in complete remission. These two cases indicate that mechanistic target of rapamycin inhibition for malignant PEComas could be a safe and successful treatment strategy in a neoadjuvant setting with an acceptable toxicity profile.

Topics: Adult; Antibiotics, Antineoplastic; Chemotherapy, Adjuvant; Female; Humans; Maintenance Chemotherapy; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Perivascular Epithelioid Cell Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Acquisition of mesenchymal properties by cancer cells is critical for their malignant behaviour, but regulators of the mesenchymal molecular machinery and how it is activated remain elusive. Here we show that clear cell renal cell carcinomas (ccRCCs) frequently utilize the Arf6-based mesenchymal pathway to promote invasion and metastasis, similar to breast cancers. In breast cancer cells, ligand-activated receptor tyrosine kinases employ GEP100 to activate Arf6, which then recruits AMAP1; and AMAP1 then binds to the mesenchymal-specific protein EPB41L5, which promotes epithelial-mesenchymal transition and focal adhesion dynamics. In renal cancer cells, lysophosphatidic acid (LPA) activates Arf6 via its G-protein-coupled receptors, in which GTP-Gα12 binds to EFA6. The Arf6-based pathway may also contribute to drug resistance. Our results identify a specific mesenchymal molecular machinery of primary ccRCCs, which is triggered by a product of autotaxin and it is associated with poor outcome of patients.

Topics: ADP-Ribosylation Factor 6; ADP-Ribosylation Factors; Adult; Aged; Aged, 80 and over; Amides; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Female; GTP-Binding Protein alpha Subunits, G12-G13; Guanine Nucleotide Exchange Factors; HEK293 Cells; Humans; Immunohistochemistry; Indoles; Isoxazoles; Kidney Neoplasms; Lysophospholipids; Male; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Nerve Tissue Proteins; Propionates; Pyridines; Pyrroles; Receptors, Lysophosphatidic Acid; Signal Transduction; Sirolimus; Sunitinib; Triazoles

We evaluated the efficacy and toxicity of mammalian target rapamycin inhibitors in Korean patients with metastatic renal cell carcinoma (mRCC) with chronic renal insufficiency not requiring dialysis.. Korean patients with mRCC and chronic renal insufficiency not requiring dialysis treated with everolimus or temsirolimus between January 2008 and December 2014 were included. Patient characteristics, clinical outcomes, and toxicities were evaluated. Overall survival (OS) and progression-free survival (PFS) durations were evaluated according to the degree of renal impairment.. Mammalian target rapamycin inhibitors were efficacious and did not increase toxicity in Korean patients with mRCC and chronic renal insufficiency not requiring dialysis.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Neoplasm Metastasis; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition.. Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated.. Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea.. The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment.

Topics: Adult; Aged; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Everolimus; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Vascular Endothelial Growth Factor A

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

Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL). The PTEN-induced BMAL1 upregulation was further confirmed using small interference RNA targeting PTEN, and in vivo conditional depletion of PTEN from the epidermis. We observed that PTEN-driven accumulation of BMAL1 was mTOR-mediated and that administration of Rapamycin, a specific mTOR inhibitor, resulted in in vivo rescue of normal levels of BMAL1. Accumulation of BMAL1 by deletion of PER2, a Period family gene, was also rescued upon in vivo administration of mTOR inhibitor. Notably, BMAL1 regulation requires mTOR regulatory protein Raptor and Rictor. These findings indicate that mTORC1 and mTORC2 complex plays a critical role in controlling BMAL1, establishing a connection between PI3K signaling and the regulation of circadian rhythm, ultimately resulting in deregulated BMAL1 in tumor cells with disrupted PI3K signaling.

Topics: Animals; ARNTL Transcription Factors; Carcinoma, Squamous Cell; Cell Line, Tumor; Circadian Rhythm; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; HeLa Cells; Humans; Lymph Nodes; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasms, Glandular and Epithelial; Oxygen; Phosphatidylinositol 3-Kinases; PTEN Phosphohydrolase; Reactive Oxygen Species; Risk Factors; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Neuroendocrine tumors (NETs) are a rare diverse group of malignancies occurring most commonly in the gastroenteropancreatic system and the lungs. The incidence of NETs is increasing worldwide; median survival for patients with metastatic NETs is 5-65 months. A growing body of evidence shows survival benefit in patients with advanced NETs (gastroenteropancreatic and lung) treated with mTOR inhibitor everolimus, with improvement in survival being demonstrated in the clinical trial and real-world setting. Everolimus has been shown to have a manageable safety profile, with the most common adverse events being stomatitis, rash, diarrhea, fatigue and infections. Due to the rarity of the condition, there are challenges in conducting clinical trials in these patients. Further research is required to clarify the role of adjuvant therapy, treatment sequencing and the use of multimodality treatments.

Topics: Clinical Trials as Topic; Combined Modality Therapy; Everolimus; Humans; Intestinal Neoplasms; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Respiratory System; Sirolimus; Stomach Neoplasms

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

To explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib.. Eight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200-600 mg once a day supplemented by S 3-4 mg taken separately, 12 h after the P dose.. Patients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4-17).. Our series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chondrosarcoma; Disease Progression; Drug Administration Schedule; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Sarcoma; Sirolimus; Sulfonamides; Survival Analysis; Treatment Outcome; Young Adult

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

The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stem-like cells sustain tumors and drive metastasis. The molecular mechanisms underlying the acquisition of CSCs and metastatic traits are not well understood. SOX9 is a transcription factor linked to stem cell maintenance and commonly overexpressed in solid cancers including colorectal cancer. In this study, we show that SOX9 levels are higher in metastatic (SW620) than in primary colorectal cancer cells (SW480) derived from the same patient. This elevated expression correlated with enhanced self-renewal activity. By gain and loss-of-function studies in SW480 and SW620 cells respectively, we reveal that SOX9 levels modulate tumorsphere formation and self-renewal ability in vitro and tumor initiation in vivo. Moreover, SOX9 regulates migration and invasion and triggers the transition between epithelial and mesenchymal states. These activities are partially dependent on SOX9 post-transcriptional modifications. Importantly, treatment with rapamycin inhibits self-renewal and tumor growth in a SOX9-dependent manner. These results identify a functional role for SOX9 in regulating colorectal cancer cell plasticity and metastasis, and provide a strong rationale for a rapamycin-based therapeutic strategy.

Topics: Cell Line, Tumor; Cell Movement; Cell Plasticity; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells; Signal Transduction; Sirolimus; SOX9 Transcription Factor

Immunosuppressive agents used postoperatively after liver transplantation (LT) for hepatocellular carcinoma (HCC) favor recurrence and metastasis. Therefore, new effective immunosuppressants are needed. This retrospective study assessed combined sirolimus and metformin on survival of HCC patients after LT. In 2001-2013, 133 HCC patients with LT were divided into four groups: sirolimus and metformin combination (Sir+Met), sirolimus monotherapy (Sir), other immunosuppressants in diabetes mellitus (DM) patients without metformin (No Sir with DM), and other immunosuppressants in patients without DM (No Sir without DM). Kaplan-Meier and Log-rank tests were used to assess survival. Cell proliferation and tumor xenograft assays were performed to disclose the mechanisms underlying the sirolimus and metformin effects. The Sir+Met group showed significantly prolonged survival compared to the other groups. The most significant cytotoxicity was seen in the Sir+Met group, with significantly decreased levels of phosphorylated PI3K, AKT, AMPK, mTOR, 4EBP1 and S6K, compared with the other groups. In agreement, Sir+Met had the highest suppressive effect on tumor growth among all groups (P<0.01). In summary, Sir+Met treatment significantly prolonged survival, likely by suppressing cell proliferation. Therefore, this combination could represent a potential routine-regimen for patients post LT.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Metformin; Mice; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Transplantation; Phosphorylation; Sirolimus; Treatment Outcome

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

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

Tumor growth and metastasis are not determined by cancer cells alone but also by a variety of stromal cells, and platelet-derived growth factor receptors (PDGF-Rs) are overexpressed by various stromal cell populations. Activation of PI3K-AKT-mTOR signaling is frequently observed in many cancer types. We investigated whether the mTOR inhibitor everolimus, alone or in combination with the PDGF-R tyrosine kinase inhibitor nilotinib, can inhibit growth and metastasis of human colon cancer. The effects of nilotinib and everolimus on tumor growth and metastasis were examined in an orthotopic mouse model of human colon cancer and a model of liver metastasis. After treatment with nilotinib (versus distilled water), the stromal reaction of xenografts growing in the cecal wall and liver was significantly decreased. After treatment with everolimus, the stromal reaction did not decrease, but tumor cell proliferation and microvessel density decreased. With the two drugs in combination, both stromal reaction and tumor cell proliferation decreased and apoptosis of tumor cells increased, resulting in remarkable inhibition of tumor growth at both the orthotopic and the metastatic site. Concurrent inhibition of tumor cells and activated stromal cells by a PDGF-R tyrosine kinase inhibitor and an mTOR inhibitor used in combination may represent a novel therapeutic approach for colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colorectal Neoplasms; Everolimus; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Platelet-Derived Growth Factor; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Sirolimus; TOR Serine-Threonine Kinases; Tumor Microenvironment; Xenograft Model Antitumor Assays

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

The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era.. We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method.. A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFNα. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus.. In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice.

Topics: Adult; Aged; Angiotensins; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Female; Humans; Indoles; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Pyrroles; Renin-Angiotensin System; Sirolimus; Sunitinib; Treatment Outcome

Mesenchymal/metaplastic breast cancers (MpBCs) are often triple-negative (TNBC), and chemo-refractory, and can harbor phosphoinositide 3-kinase (PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity.. Patients with mesenchymal/MpBC treated with temsirolimus-based regimens were evaluated. Mutational analyses [polymerase chain reaction (PCR)-based DNA sequencing method, mass spectrometric detection (Sequenom MassARRAY), or next-generation sequencing] as well as loss of phosphatase and tensin homolog (PTEN) (immunohistochemistry) were performed (archived tissue when available).. Twenty-three patients (one of whom was on two separate trials) were treated using temsirolimus-containing regimens: temsirolimus alone (n = 1 patient) or combined with the following: liposomal doxorubicin and bevacizumab (DAT, n = 18); liposomal doxorubicin (DT, n = 1); paclitaxel and bevacizumab (TAT, n = 2); paclitaxel (TT, n = 1); carboplatin and bevacizumab (CAT, n = 1). Response rate [complete response (CR) + partial response (PR)] was 25% across all regimens; 32% in the anthracycline-based regimens [DAT and DT (CR = 2, PR = 4; N = 19)]. An additional two patients achieved stable disease (SD) ≥6 months [total SD ≥6 months/CR/PR = 8 (33%)]. Molecular aberrations in the PI3K pathway were common: PIK3CA mutation = 6/15 (40%), PTEN mutation = 3/11 (27%), and PTEN loss = 2/11 (18%). A point mutation in the NF2 gene (K159fs*16; NF2 alterations can activate mTor) was found in one patient who attained CR (3+ years). Of the eight patients who achieved SD ≥6 months/CR/PR, all 4 patients with available tissue had a molecular aberration that activate the PIK3CA/Akt/mTOR axis: PIK3CA mutation = 2; PTEN loss = 1; NF2 aberration = 1.. DAT has activity in MpBCs including complete CRs. Molecular aberrations that can activate the PI3 K/Akt/mTOR axis are common in MpBC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Carboplatin; Class I Phosphatidylinositol 3-Kinases; Doxorubicin; Female; Follow-Up Studies; Humans; Mesoderm; Metaplasia; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Paclitaxel; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Polyethylene Glycols; Polymerase Chain Reaction; Prognosis; PTEN Phosphohydrolase; Sirolimus; Survival Rate; Young Adult

Autophagy is an important oncotarget that can be modulated during anti-cancer therapy. Enhancing autophagy using chemotherapy and rapamycin (Rapa) treatment and then inhibiting it using hydroxychloroquine (HCQ) could synergistically improve therapy outcome in cancer patients. It is still unclear whether addition of Rapa and HCQ to chemotherapy could be used for reversing drug resistance.. Twenty-five stage IV cancer patients were identified. They had no clinical response to first-line metronomic chemotherapy; the patients were salvaged by adding an autophagy inducer (Rapa, 2 mg/day) and an autophagosome inhibitor (HCQ, 400 mg/day) to their current metronomic chemotherapy for at least 3 months. Patients included 4 prostate, 4 bladder, 4 lung, 4 breast, 2 colon, and 3 head and neck cancer patients as well as 4 sarcoma patients.. Chemotherapy was administered for a total of 137 months. The median duration of chemotherapy cycles per patient was 4 months (95% confidence interval, 3-7 months). The overall response rate to this treatment was of 40%, with an 84% disease control rate. The most frequent and clinically significant toxicities were myelotoxicities. Grade ≥3 leucopenia occurred in 6 patients (24%), grade ≥3 thrombocytopenia in 8 (32%), and anemia in 3 (12%). None of them developed febrile neutropenia. Non-hematologic toxicities were fatigue (total 32%, with 1 patient developing grade 3 fatigue), diarrhea (total 20%, 1 patient developed grade 3 fatigue), reversible grade 3 cardiotoxicity (1 patient), and grade V liver toxicity from hepatitis B reactivation (1 patient).. Our results of Rapa, HCQ and chemotherapy triplet combination suggest autophagy is a promising oncotarget and warrants further investigation in phase II studies.

Topics: Administration, Metronomic; Aged; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Dose-Response Relationship, Drug; Female; Humans; Hydroxychloroquine; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Pilot Projects; Salvage Therapy; Sirolimus; Treatment Outcome

The normal process of epithelial mesenchymal transition (EMT) is subverted by carcinoma cells to facilitate metastatic spread. Cancer cells rarely undergo a full conversion to the mesenchymal phenotype, and instead adopt positions along the epithelial-mesenchymal axis, a propensity we refer to as epithelial mesenchymal plasticity (EMP). EMP is associated with increased risk of metastasis in breast cancer and consequent poor prognosis. Drivers towards the mesenchymal state in malignant cells include growth factor stimulation or exposure to hypoxic conditions.. We have examined EMP in two cell line models of breast cancer: the PMC42 system (PMC42-ET and PMC42-LA sublines) and MDA-MB-468 cells. Transition to a mesenchymal phenotype was induced across all three cell lines using epidermal growth factor (EGF) stimulation, and in MDA-MB-468 cells by hypoxia. We used RNA sequencing to identify gene expression changes that occur as cells transition to a more-mesenchymal phenotype, and identified the cell signalling pathways regulated across these experimental systems. We then used inhibitors to modulate signalling through these pathways, verifying the conclusions of our transcriptomic analysis.. We found that EGF and hypoxia both drive MDA-MB-468 cells to phenotypically similar mesenchymal states. Comparing the transcriptional response to EGF and hypoxia, we have identified differences in the cellular signalling pathways that mediate, and are influenced by, EMT. Significant differences were observed for a number of important cellular signalling components previously implicated in EMT, such as HBEGF and VEGFA. We have shown that EGF- and hypoxia-induced transitions respond differently to treatment with chemical inhibitors (presented individually and in combinations) in these breast cancer cells. Unexpectedly, MDA-MB-468 cells grown under hypoxic growth conditions became even more mesenchymal following exposure to certain kinase inhibitors that prevent growth-factor induced EMT, including the mTOR inhibitor everolimus and the AKT1/2/3 inhibitor AZD5363.. While resulting in a common phenotype, EGF and hypoxia induced subtly different signalling systems in breast cancer cells. Our findings have important implications for the use of kinase inhibitor-based therapeutic interventions in breast cancers, where these heterogeneous signalling landscapes will influence the therapeutic response.

Topics: Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Epidermal Growth Factor; Epithelial-Mesenchymal Transition; Everolimus; Female; Humans; Immunosuppressive Agents; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Lymphangioleiomyomatosis (LAM) is a progressive, rare interstitial lung disease that almost exclusively affects women. It is caused by a mutation in one of the tuberous sclerosis genes, TSC1 or TSC2, and constitutive activation of the mammalian target of rapamycin (mTOR) pathway in smooth muscle-like cells (LAM cells). The heightened proliferation and accumulation of LAM cells leads to the destruction of lung tissue.. In the present study, we developed a cell line (S-LAM1) derived from a chylous effusion obtained from a patient with sporadic, pulmonary LAM and evaluated its phenotype using immunofluorescence, flow cytometry, and an image stream system. Ultrastructure was assessed using a transmission electron microscope. To assess the ability of LAM cells to move and migrate (which is strictly associated with the ability to metastasize), we carried-out a real-time polymerase chain reaction (PCR) array analysis of 84 genes involved in cell motility. In order to evaluate the effect of rapamycin, a natural inhibitor of mTOR kinase, on S-LAM1 cells, a sulforhodamine B cell viability assay was performed with different concentrations of rapamycin.. The phenotype of these cells is consistent with the biology of LAM cells. S-LAM1 cells present combined smooth muscle, melanocytic, and lymphatic endothelium lineage, as well as the presence of mesenchymal differentiation markers. A particular pattern of gene expression, including high expression of ezrin (EZR), myosin heavy chain 10, non-muscle (MYH10), and myosin light chain kinase (MYLK) and a greatly decreased expression of supervillin (SVIL), when compared to controls, indicates a high potential motility activity, especially of cell spreading. Rapamycin significantly, although only partially, inhibited S-LAM1 cell proliferation in vitro, and should, perhaps, be considered in the future in combination with other agents.

Topics: Adult; Animals; Cell Movement; Cell Proliferation; Cell Survival; Female; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Mice; Microscopy, Electron, Transmission; Mutation; Myocytes, Smooth Muscle; Neoplasm Metastasis; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.

Topics: Animals; Apoptosis; Benzamides; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; ErbB Receptors; Erlotinib Hydrochloride; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Neoplasm Metastasis; Piperazines; Pyrazoles; Receptor, Fibroblast Growth Factor, Type 2; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Stem Cell Assay; Tumor Suppressor Proteins

We hypothesized that lymphoid-selective host conditioning and subsequent adoptive transfer of sirolimus-resistant allogeneic T cells (T-Rapa), when combined with high-dose sirolimus drug therapy in vivo, would safely achieve antitumor effects while avoiding GVHD.. Patients (n = 10) with metastatic renal cell carcinoma (RCC) were accrued because this disease is relatively refractory to high-dose conditioning yet may respond to high-dose sirolimus. A 21-day outpatient regimen of weekly pentostatin (P; 4 mg/m(2)/dose) combined with daily, dose-adjusted cyclophosphamide (C; ≤200 mg/d) was designed to deplete and suppress host T cells. After PC conditioning, patients received matched sibling, T-cell-replete peripheral blood stem cell allografts, and high-dose sirolimus (serum trough target, 20-30 ng/mL). To augment graft-versus-tumor (GVT) effects, multiple T-Rapa donor lymphocyte infusions (DLI) were administered (days 0, 14, and 45 posttransplant), and sirolimus was discontinued early (day 60 posttransplant).. PC conditioning depleted host T cells without neutropenia or infection and facilitated donor engraftment (10 of 10 cases). High-dose sirolimus therapy inhibited multiple T-Rapa DLI, as evidenced by stable mixed donor/host chimerism. No antitumor responses were detected by RECIST criteria and no significant classical acute GVHD was observed.. Immune-selective PC conditioning represents a new approach to safely achieve alloengraftment without neutropenia. However, allogeneic T cells generated ex vivo in sirolimus are not resistant to the tolerance-inducing effects of in vivo sirolimus drug therapy, thereby cautioning against use of this intervention in patients with refractory cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cyclophosphamide; Female; Graft vs Tumor Effect; Humans; Immunophenotyping; Immunotherapy, Adoptive; Lymphocyte Depletion; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Pentostatin; Peripheral Blood Stem Cell Transplantation; Phenotype; Sirolimus; T-Lymphocyte Subsets; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

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

mTORC1 is a master regulator of cell growth and proliferation, and an established anticancer drug target. Aberrant mTORC1 signaling is common in hepatocellular carcinoma (HCC), but the underlying mechanism remains elusive. Rab1A is a newly identified mTORC1 activator that mediates an alternative amino acid (AA) signaling branch to Rag GTPases. Because liver is a physiological hub for nutrient sensing and metabolic homeostasis, we investigated the possible role of Rab1A in HCC. We found that Rab1A is frequently overexpressed in HCC, which enhances hyperactive AA-mTORC1 signaling, promoting malignant growth and metastasis of HCC in vitro and in vivo. Moreover, aberrant Rab1A expression is closely associated with poor prognosis. Strikingly, aberrant Rab1A overexpression leads to increased rapamycin sensitivity, indicating that inappropriate activation of AA signaling is a cancer-driving event in HCC. Our findings further suggest that Rab1A is a valuable biomarker for prognosis and personalized mTORC1-targeted therapy in liver cancer.

Topics: Aged; Amino Acids; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Survival; Cohort Studies; Female; Gene Dosage; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Liver Neoplasms; Male; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Multiprotein Complexes; Neoplasm Invasiveness; Neoplasm Metastasis; Prognosis; rab1 GTP-Binding Proteins; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Wound Healing

Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan's National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine.

Topics: Adult; Animals; Autophagy; Cancer Vaccines; Cell Differentiation; Cell Line, Tumor; Dendritic Cells; Female; Humans; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Middle Aged; Naphthoquinones; Neoplasm Metastasis; Neoplasms; Sirolimus; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Young Adult

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Everolimus; Giant Cell Tumors; Humans; Joint Capsule; Male; Middle Aged; Neoplasm Metastasis; Receptors, Somatomedin; Shoulder Joint; Sirolimus; Soft Tissue Neoplasms; Tendons; TOR Serine-Threonine Kinases; Treatment Outcome

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

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

The life expectancy in metastatic renal cell carcinoma patients treated with targeted therapies can be influenced by the time spent on treatment, and the current focus of clinical research in this field appears to be on extending the time on treatment while limiting toxicities. It has been proposed that a strategy based on the sequential administration of two tyrosine kinase inhibitors could result in unacceptable cumulative toxicity for many metastatic renal cell carcinoma patients, while switching to a mTOR inhibitor does not. However, a definite consensus on this issue has not been reached. As very little information from head-to-head studies is available, clinicians have to base their treatment decisions on existing evidence, with an obvious preference for high-quality studies. Some recent studies have provided new insights into the issue of cumulative toxicity of second-line targeted therapies in metastatic renal cell carcinoma patients. In this article, we discuss the evidence emerging from the randomized AXIS and RECORD-3 trials.

Topics: Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor Receptor-1

We report the identification of an FBXW7 mutation in a patient with adenocarcinoma of the lung, whose tumor had previously been shown to be EGFR and ALK wild type and who had previously progressed on multiple lines of systemic therapy. She experienced both clinical and radiographic benefit from treatment with the mTOR inhibitor temsirolimus.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cell Cycle Proteins; Drug Resistance, Neoplasm; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Female; Glutamates; Guanine; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Middle Aged; Molecular Targeted Therapy; Motor Activity; Mutation; Neoplasm Metastasis; Pemetrexed; Recurrence; Remission Induction; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases; Weight Gain

To investigate the molecular mechanism of pancreatic cancer cell resistance to mammalian target of rapamycin (mTOR) inhibitor RAD001, and explore a feasible therapeutic strategy to overcome the resistance in patients with pancreatic cancer.. Western blotting was conducted to find out whether RAD001 induced c-Raf-ERK feedback activation and to identify whether RAD001 in combination with c-Raf inhibitor sorafenib could effectively block the feedback activation of c-Raf and downstream proteins. Sulphorhodamine B (SRB) colorimetric assay and colony formation were used to detect the effect of the combination treatment on cell growth and proliferation; finally, the effect on mouse subcutaneous xenografts was examined to confirm the efficacy of the combination treatment in vivo.. RAD001 effectively inhibited the expressions of mTORC1 and its downstream proteins, and induced the feedback activation of c-Raf. Whereas, RAD001 combined with c-Raf inhibitor sorafenib eliminated RAD001-induced activation of c-Raf-ERK pathway and reversed pancreatic cancer cell resistance to RAD001; compared with the RAD001 alone, sorafenib had a synergistical inhibitory effect with RAD001. And the tumor growth inhibitory effect of the combination was also proved in mouse subcutaneous xenografts in vivo.. RAD001-induced c-Raf-ERK feedback activation contributes to pancreatic cancer cell resistance to RAD001. Targeting of c-Raf may improve the therapeutic efficacy of RAD001 in patients with pancreatic cancer.

Topics: Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Activation; Everolimus; Humans; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Metastasis; Pancreatic Neoplasms; Proto-Oncogene Proteins c-raf; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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

The tumor microenvironment plays an important role in the tumor's progression and metastasis. Therefore, successful alteration of this delicate setting against the tumor's favor can open a window for therapeutic efficacy. We have developed a modality to bring about treatment-induced alterations in the tumor microenvironment by employing the synergistic effects between two drugs. Co-delivery of rapamycin (RAPA), an mTOR inhibitor that may offer notable therapy through antiangiogenic activity, alongside cisplatin can foster significant potency as RAPA sensitizes A375 melanoma cells to cisplatin therapy through microenvironment modulation. However, encapsulation of these drugs into poly(lactic-co-glycolic acid) (PLGA) NPs was inefficient due to the incompatibility between the two free drugs and the polymer matrix. Here, we show cisplatin can be made hydrophobic by coating a nanoprecipitate (cores) of the drug with dioleoylphosphatidic acid (DOPA). These DOPA coated cisplatin cores are compatible with PLGA and can be coencapsulated in PLGA NPs alongside RAPA at a molar ratio to promote synergistic antitumor activity. The presence of the cisplatin cores significantly improved the encapsulation of RAPA into PLGA NPs. Furthermore, PLGA NPs containing both cisplatin cores and RAPA induced significant apoptosis on A375-luc human melanoma cells in vitro. Additionally, they inhibited the growth of A375-luc melanoma in a xenograft tumor model through modulation of the tumor vasculature and permitted enhanced penetration of NPs into the tumor.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chromatography, High Pressure Liquid; Cisplatin; Dihydroxyphenylalanine; Disease Progression; Drug Carriers; Humans; In Situ Nick-End Labeling; Lactic Acid; Melanoma; Mice; Nanoparticles; Nanotechnology; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Platelet Endothelial Cell Adhesion Molecule-1; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Sirolimus; Skin Neoplasms; Solvents; Tumor Microenvironment

Everolimus in combination with exemestane significantly improved progression-free survival compared to exemestane alone in patients previously treated with non-steroidal aromatase inhibitors in the BOLERO-2 trial. As a result, this combination has been approved by the food and drug administration to treat postmenopausal women with hormone receptor positive and HER2 negative metastatic breast cancer. A cost-effectiveness analysis was conducted to determine whether everolimus represents good value for money, utilizing data from BOLERO-2. A decision-analytic model was used to estimate the incremental cost-effectiveness ratio between treatment arms of the BOLERO-2 trial. Costs were obtained from the Center for Medicare Services drug payment table and physician fee schedule. Benefits were expressed as quality-adjusted progression-free survival weeks (QAPFW) and quality-adjusted progression-free years (QAPFY), with utilities/disutilities derived from the literature. Deterministic and probabilistic sensitivity analyses were performed. A willingness to pay threshold of 1-3 times the per capita gross domestic product was adopted, as per the definition of the World Health Organization. The U.S. per capita gross domestic product in 2013 was $49,965; thus, a threshold varying between $49,965 and $149,895 was considered. Everolimus/exemestane had an incremental benefit of 11.88 QAPFW (0.22 QAPFY) compared to exemestane and an incremental cost of $60,574. This translated into an ICER of $265,498.5/QAPFY. Univariate sensitivity analyses showed important variations of the ICER, ranging between $189,836.4 and $530,947/QAPFY. A tornado analysis suggested that the key drivers of our model, by order of importance, included health utility value for stable disease, everolimus acquisition costs, and transition probabilities from the stable to the progression states. The Monte-Carlo simulation showed results that were similar to the base-case analysis. This cost-effectiveness analysis showed that everolimus plus exemestane is not cost-effective compared to exemestane alone. Further research is needed to investigate the cost-effectiveness of the drug combination within sub-groups of the population studied in BOLERO-2.

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cost-Benefit Analysis; Disease Progression; Disease-Free Survival; Everolimus; Female; Humans; Markov Chains; Neoplasm Metastasis; Sirolimus

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

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

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

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

Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%).. Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases.. At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months).. Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases.

Topics: Aged; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase III as Topic; Everolimus; Exanthema; Fatigue; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Middle Aged; Multicenter Studies as Topic; Neoplasm Metastasis; Placebos; Postmenopause; Prognosis; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Steroid; Sirolimus; Stomatitis; Treatment Outcome; Viscera

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

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

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 mechanisms that regulate hematopoietic stem cell (HSC) dormancy and self-renewal are well established and are largely dependent on signals emanating from the HSC niche. Recently, we found that prostate cancer (PCa) cells target the HSC niche in mouse bone marrow (BM) during metastasis. Little is known, however, as to how the HSC niche may regulate dormancy in cancer cells. In this study, we investigated the effects of TANK binding kinase 1 (TBK1) on PCa dormancy in the BM niche. We found that binding with niche osteoblasts induces the expression of TBK1 in PCa cells PC3 and C4-2B. Interestingly, TBK1 interacts with mammalian target of rapamycin (mTOR) and inhibits its function. Rapamycin, an mTOR inhibitor, induces cell cycle arrest of PCa cells and enhances chemotherapeutic resistance of PCa cells. As a result, the knockdown of TBK1 decreases PCa stem-like cells and drug resistance in vitro and in vivo. Taken together, these results strongly indicate that TBK1 plays an important role in the dormancy and drug resistance of PCa.

Topics: AC133 Antigen; Animals; Antigens, CD; Bone Marrow; Bone Marrow Cells; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Glycoproteins; Hematopoietic Stem Cells; Humans; Hyaluronan Receptors; I-kappa B Kinase; Male; Mice; Mice, SCID; Neoplasm Metastasis; Osteoblasts; Peptides; Prostatic Neoplasms; Protein Serine-Threonine Kinases; RNA Interference; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Novel methods to control and treat metastatic breast cancer are needed. Interleukin (IL)-15 is a promising cytokine for cancer immunotherapy, and everolimus is an orally administered mammalian target of rapamycin (mTOR) inhibitor, which is already approved for cancer treatment. In the present study, we investigated the efficacy of IL-15 gene therapy and explored the possibility of combining IL-15 therapy with everolimus to treat metastatic breast cancer.. A plasmid encoding IL-15 and everolimus were given to mice inoculated with 4 T1 mouse breast cancer cells. Tumor size and metastasis were monitored to assess the effect of different treatment regimens. Immunohistochemistry was used to detect CD4⁺, CD8⁺ and NKG2D⁺ cells and also the expression of Ki-67 in tumor tissue; these analyses helped establish the immunization status and tumor proliferation rate of different treatment groups. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed to assess cellular apoptosis in tumor tissues.. Both IL-15 and everolimus significantly decreased tumor size. IL-15 gene therapy increased the proportion of CD4⁺ T and natural killer (NK) cells but had no effect on CD8⁺ T cells. By contrast, everolimus decreased the number of CD8⁺ T cells but had no effect on CD4⁺ T and NK cells compared to the control group. Both IL-15 and everolimus decreased expression of Ki-67 and increased rates of apoptosis. Although effective on their own, no synergistic effect was observed with a combined treatment of everolimus and IL-15 gene therapy.. IL-15 gene therapy was potentially useful for the treatment of metastatic breast cancer. The possibility of combining immunotherapy with everolimus requires further study.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line; Cell Proliferation; Combined Modality Therapy; Disease Models, Animal; Dose-Response Relationship, Drug; Everolimus; Female; Gene Order; Genetic Therapy; Genetic Vectors; Immunotherapy; Interleukin-15; Mice; Neoplasm Metastasis; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden

In one trial, combination therapy with everolimus and exemestane prolonged progression-free survival a few months (on the basis of radiological studies) compared with exemestane alone, which is not the standard treatment. However, the addition of everolimus greatly increased the incidence of serious adverse effects. As of mid-2013, the effect on overall survival is uncertain.

Topics: Antineoplastic Agents; Breast Neoplasms; Everolimus; Female; Humans; Neoplasm Metastasis; Sirolimus

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Breast; Breast Neoplasms; Drug Discovery; Everolimus; Female; HSP90 Heat-Shock Proteins; Humans; Immunoconjugates; Neoplasm Metastasis; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Quinolines; Sirolimus

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

Inhibition of mTOR is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everolimus) results in the occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was administered twice weekly for 4.5 weeks as a single treatment or combined with [(177)Lu-DOTA,Tyr3]octreotate ((177)Lu-DOTATATE), where the latter targets the somatostatin receptor-2. The hypothesized synergistic therapeutic effect of RAD001 combined with (177)Lu-DOTATATE was, however, not observed in our experiments. The combination was shown to be less effective than (177)Lu-DOTATATE alone. Unexpectedly, tumor metastasis was observed in 77% of the subjects treated with RAD001, either alone or as part of the combination treatment. This was a striking effect, because metastasis did not occur in control or (177)Lu-DOTATATE-treated animals, including those where the primary tumor was surgically removed. These findings may be important clinically among noncompliant patients or patients that discontinue RAD001 therapy because of adverse effects.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Cell Line, Tumor; Disease Models, Animal; Everolimus; Humans; Male; Mice; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Sirolimus; TOR Serine-Threonine Kinases

Topics: Anti-Infective Agents; Brain Abscess; Everolimus; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Insulinoma; Middle Aged; Neoplasm Metastasis; Nocardia; Nocardia Infections; Pancreatic Neoplasms; Sirolimus; Trimethoprim, Sulfamethoxazole Drug Combination

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

Epidemiological studies have indicated that obesity is associated with colorectal cancer. The obesity hormone leptin is considered as a key mediator for cancer development and progression. The present study aims to investigate regulatory effects of leptin on colorectal carcinoma. The expression of leptin and its receptor Ob-R was examined by immunohistochemistry in 108 Chinese patients with colorectal carcinoma. The results showed that leptin/Ob-R expression was significantly associated with T stage, TNM stage, lymph node metastasis, distant metastasis, differentiation and expression of p-mTOR, p-70S6 kinase, and p-Akt. Furthermore, the effects of leptin on proliferation and apoptosis of HCT-116 colon carcinoma cells were determined. The results showed that leptin could stimulate the proliferation and inhibit the apoptosis of HCT-116 colon cells through the PI3K/Akt/mTOR pathway. Ly294002 (a PI3K inhibitor) and rapamycin (an mTOR inhibitor) could prevent the regulatory effects of leptin on the proliferation and apoptosis of HCT-116 cells via abrogating leptin-mediated PI3K/Akt/mTOR pathway. All these results indicated that leptin could regulate proliferation and apoptosis of colorectal carcinoma through the PI3K/Akt/ mTOR signalling pathway.

Topics: Apoptosis; Asian People; Cell Proliferation; Chromones; Colorectal Neoplasms; Humans; Immunohistochemistry; Leptin; Morpholines; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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

Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Capecitabine; Clinical Trials, Phase III as Topic; Deoxycytidine; Disease-Free Survival; Everolimus; Female; Fluorouracil; Humans; Indoles; Neoplasm Metastasis; Neovascularization, Pathologic; Niacinamide; Paclitaxel; Phenylurea Compounds; Pyrroles; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

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

Cancer drugs often induce dramatic responses in a small minority of patients. We used whole-genome sequencing to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity. These results demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs.

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Codon, Nonsense; Disease-Free Survival; Drug Resistance, Neoplasm; Everolimus; Genome-Wide Association Study; Genome, Human; Humans; Mechanistic Target of Rapamycin Complex 1; Molecular Targeted Therapy; Multiprotein Complexes; Neoplasm Metastasis; Neurofibromin 2; Proteins; Sequence Deletion; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Urinary Bladder Neoplasms

Metastasis is a major cause of death from malignant diseases, and the underlying mechanisms are still largely not known. A detailed probe into the factors which may regulate tumour invasion and metastasis contributes to novel anti-metastatic therapies. We previously identified a novel metastasis-associated gene 1 (mag-1) by means of metastatic phenotype cloning. Then we characterized the gene expression profile of mag-1 and showed that it promoted cell migration, adhesion and invasion in vitro. Importantly, the disruption of mag-1 via RNA interference not only inhibited cellular metastatic behaviours but also significantly reduced tumour weight and restrained mouse breast cancer cells to metastasize to lungs in spontaneous metastatic assay in vivo. Furthermore, we proved that mag-1 integrates dual regulating mechanisms through the stabilization of HIF-1α and the activation of mTOR signalling pathway. We also found that mag-1-induced metastatic promotion could be abrogated by mTOR specific inhibitor, rapamycin. Taken together, the findings identified a direct role that mag-1 played in metastasis and implicated its function in cellular adaptation to tumour microenvironment.

Topics: 1-Acylglycerol-3-Phosphate O-Acyltransferase; Animals; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Chlorocebus aethiops; COS Cells; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasm Metastasis; RNA Interference; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcriptome; Tumor Microenvironment

Topics: Carcinoma, Renal Cell; Humans; Indoles; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prognosis; Pyrroles; Sirolimus; Sorafenib; Sunitinib; Survival Analysis

Advances in targeted therapies have improved progression-free and overall survival in women with metastatic breast cancer; however, regardless of efficacy, resistance almost always occurs eventually. Upregulation of the PI3K/AKT/mTOR pathway, which promotes cell growth and proliferation, is a means of escaping responsiveness to hormone therapy in hormone receptor-positive disease, or trastuzumab in HER2-positive disease. Everolimus, an inhibitor of mTOR, has shown promise in early clinical trials in metastatic breast cancer and is currently being studied in larger Phase II and III clinical trials, combined with hormone therapy or trastuzumab with or without cytotoxic chemotherapy. In this article, we discuss the mechanistic and preclinical data for everolimus, efficacy and safety results of clinical trials, and the landscape looking forward.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Receptor, ErbB-2; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Trastuzumab; Treatment Outcome

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

Radiation-induced gastritis is an infrequent cause of gastrointestinal bleeding. It is a serious complication arising from radiation therapy, and the standard treatment method has not been established. The initial injury is characteristically acute inflammation of gastric mucosa. We presented a 46-year-old male patient with hemorrhagic gastritis induced by external radiotherapy for metastatic retroperitoneal lymph node of hepatocellular carcinoma. The endoscopic examination showed diffuse edematous hyperemicmucosa with telangiectasias in the whole muscosa of the stomach and duodenal bulb. Multiple hemorrhagic patches with active oozing were found over the antrum. Anti-secretary therapy was initiated for hemostasis, but melena still occurred off and on. Finally, he was successfully treated by prednisolone therapy. We therefore strongly argue in favor of perdnisolone therapy to effectively treat patients with radiation-induced hemorrhagic gastritis.

Topics: Carcinoma, Hepatocellular; Endoscopy; Gastritis; Gastrointestinal Hemorrhage; Hemostasis; Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Metastasis; Prednisolone; Radiation Injuries; Sirolimus

Everolimus (RAD001, Afinitor) is an mTORC1 pathway inhibitor, and vatalanib (PTK/ZK) is a pan VEGF-R tyrosine kinase inhibitor (TKI). These two drugs have been shown to have overlapping but also distinct anti-angiogenic effects. Consequently, we investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of their combination in vivo.. Murine melanoma B16/BL6 cells were grown orthotopically in BL6/C57 mice by injection into the derma of both ears to create a primary tumour which metastasized rapidly to the cervical lymph nodes. Mice were treated daily p.o. with PTK/ZK (100 mg/kg) or everolimus (1 mg/kg) or their combination, and anti-tumour efficacy (PD) assessed. In the same model, plasma PK of everolimus was measured following single doses of the monotherapy or combination schedules.. Two independent experiments showed that combination of everolimus and PTK/ZK caused at least additive increases in anti-tumour activity compared to either monotherapy, without increases in toxicity. Pooling the data to improve the statistical power demonstrated the interactions to be synergistic. PK modelling showed that although PTK/ZK increased everolimus plasma concentrations by about twofold, this PK drug-drug interaction could not account for the increased anti-tumour effect of the combination. Modelling of the PTK/ZK dose-response curve in this model suggested that any effect of everolimus on the PK of PTK/ZK was unlikely to affect efficacy. Measurement of changes in tumour and plasma VEGF levels at the endpoint of therapy confirmed earlier observations of differential effects of these two agents.. The combination of everolimus and PTK/ZK hold promise for the treatment of human cancers.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Everolimus; Female; Mechanistic Target of Rapamycin Complex 1; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Models, Biological; Multiprotein Complexes; Neoplasm Metastasis; Phthalazines; Proteins; Pyridines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; TOR Serine-Threonine Kinases

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

Mammalian target of rapamycin suppression by rapamycin inhibits tumor growth and neovascularization via cyclooxygenase-2 (COX-2) downregulation with no effect on lung metastases. We hypothesize that combining a selective COX-2 antagonist (celecoxib) with rapamycin would decrease lung metastases.. Ewing sarcoma cells (SK-NEP-1) were surgically implanted into the left kidney of athymic mice (n = 40). The mice were divided into 4 treatment groups (control, rapamycin only, celecoxib only, and combination) and then killed at 6 weeks. Primary tumors were weighed. Vasculature was examined using lectin angiography and immunohistochemistry, and lung metastases were examined using H&E and CD99 immunostaining. Tumor weight and lung metastases were analyzed.. Mean primary tumor weights were significantly reduced in the rapamycin-treated groups but not in the celecoxib-only group. Lectin angiography and endothelial markers immunostaining showed markedly decreased vascularity in the rapamycin-treated groups but not in the celecoxib-only group. Celecoxib-treated groups showed significantly fewer mice with lung metastases than non-celecoxib-treated groups.. Celecoxib prevents lung metastasis in a murine model of Ewing sarcoma with no effect on tumor size or neovascularization. Cyclooxygenase-2 may represent a future potential target for metastatic disease prevention.

Topics: Angiogenesis Inhibitors; Animals; Celecoxib; Cell Line, Tumor; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Down-Regulation; Drug Therapy, Combination; Female; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; Pyrazoles; Sarcoma, Ewing; Sirolimus; Sulfonamides

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

Mammalian target of rapamycin inhibitor everolimus administered to four insulinoma patients rapidly controlled hypoglycemia (Kulke et al., N Engl J Med 2009;360:195-197). We wanted to identify the kinetics of everolimus effects on controlling hypoglycemia and understand underlying mechanisms.. Three consecutive patients with a metastasized symptomatic insulinoma were started on 100 μg of octreotide subcutaneously three times daily. Because of persisting hypoglycemias, treatment with daily 10 mg of oral everolimus was initiated. Serial plasma glucose levels and serum insulin levels were measured. Computer tomography (CT) scans were performed before and after 2 and 5 months of treatment. [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) scans, to visualize glucose metabolism, were made before and after 2 weeks, 5 weeks, and 5 months of treatment. The ¹⁸F-FDG uptake was quantified as the maximum standardized uptake value.. All patients achieved control of hypoglycemia on everolimus within 14 days. Insulin levels were 2.5- to 6.3-fold elevated before start of treatment and declined 14%-64% after 4 weeks of treatment. CT scans showed stable disease at 2 months in all patients, with progressive disease after 5 months in one. Before treatment, both the tumor lesions and the muscles and myocardium showed high ¹⁸F-FDG uptake. Everolimus reduced tumor and muscle ¹⁸F-FDG uptake after 2 weeks by 26% ± 14% and 19% ± 41%, and after 5 months by 31% ± 13% and 27% ± 41%.. Everolimus normalizes plasma glucose levels in metastatic insulinoma within 14 days, coinciding with a lower glucose uptake in tumor and muscles and declining (pro)insulin levels. This effect on tumor as well as normal tissues explains the rapid controlling of hypoglycemia.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Blood Glucose; Everolimus; Female; Fluorodeoxyglucose F18; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Positron-Emission Tomography; Sirolimus; Tomography, X-Ray Computed; 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: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Humans; Interferon-alpha; Neoplasm Metastasis; Sirolimus

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

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

Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multi-targeting approach against PI3K, mTORC1/2 and MAPK.

Topics: Adaptor Proteins, Signal Transducing; Apoptosis; Carcinoma, Transitional Cell; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Enzyme Activation; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphoproteins; Proto-Oncogene Proteins c-akt; Quinolines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Urinary Bladder Neoplasms

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Disease-Free Survival; Doxorubicin; Humans; Ifosfamide; Neoplasm Metastasis; Osteosarcoma; Randomized Controlled Trials as Topic; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases

Topics: Carcinoma, Renal Cell; Everolimus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Metastasis; Radiography; Reflex Sympathetic Dystrophy; Sirolimus

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

Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.

Topics: Animals; Antibiotics, Antineoplastic; Colonic Neoplasms; Disease Models, Animal; Disease Progression; Genes, APC; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Mutation; Neoplasm Metastasis; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins p21(ras); Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Akt and mTOR are therapeutic targets for the treatment of cancer. The effects of inhibiting mTOR, with rapamycin, and Akt, with A-443654, concurrently, on cell morphology, cell proliferation, the cell cycle, and apoptosis were examined using the benign MCF10A and malignant MCF10CA1a human breast epithelial cells. Rapamycin and A-443654 in combination produced the greatest morphological changes and inhibited cell proliferation by G2/M arrest. Rapamycin and A-443654 in combination induced apoptosis at earlier times and at lower A-443654 concentrations in MCF10CA1a tumor cells than in the benign MCF10A cells. Rapamycin and A-443654 increased p53 and p15(INK4B) protein levels, decreased anti-apoptotic Bcl-2 levels, and increased Bad levels in the MCF10CA1a tumor cells by approximately 5-fold. These results suggest that the combined inhibition of Akt and mTOR may have beneficial therapeutic and safety margin effects.

Topics: Breast Neoplasms; Cell Cycle; Cell Division; Cell Line, Tumor; Enzyme Activation; Epithelial Cells; Female; Fibrocystic Breast Disease; Flow Cytometry; Humans; Immunoblotting; Indazoles; Indoles; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Sirolimus; Survivors

Malignancies are a well-known complication of immunosuppressive therapy among renal transplant recipients, representing an important cause of long-term morbidity and mortality. Rapamycin has been shown to limit the proliferation of a number of malignant cell lines in vivo and in vitro.. Fifteen patients developed the following malignancies at a mean of 90.3 months (range = 10-252) after kidney transplantation: metastatic gastric cancer (n = 1), metastatic colon cancer (n = 1), bilateral nephrourothelioma (n = 1), skin cancer (n = 2), Kaposi's sarcoma (n = 2), posttransplant lymphoproliferative disorder (PTLD; n = 4), renal cell carcinoma T1 (n = 1), MALT lymphoma (n = 1), intramucous colon carcinoma (n = 1), liposarcoma of the spermatic cord (n = 1). After the diagnosis of malignancy, the patients were switched from calcineurin inhibitor-based immunosuppression to rapamycin (monotherapy, n = 3), or associated with steroids (n = 6) or with mycophenolate mofetil (n = 6).. Both patients with metastatic cancer underwent chemotherapy but succumbed after 6 and 13 months. Two patients with PTLD who underwent chemotherapy died after 12 and 36 months. At a mean follow-up of 32.7 months (range = 7-56), the remaining 11 patients are cancer-free. Two patients lost their grafts after 24 and 36 months after the switch due to chronic rejection. Renal graft function remained stable in all other patients from diagnosis throughout follow-up.. Our observations suggested that rapamycin-based immunosuppression offers the possibility for regression of nonmetastatic tumors. Nevertheless, it is difficult to assess whether tumor regression was due to rapamycin treatment or to the reduced immunosuppression.

Topics: Cell Division; Cell Line, Tumor; Colonic Neoplasms; Genital Neoplasms, Male; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Liposarcoma; Male; Neoplasm Metastasis; Neoplasms; Sirolimus; Skin Neoplasms; Stomach Neoplasms

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Cytotoxins; Embolization, Therapeutic; Europe; Female; Follow-Up Studies; Gastrointestinal Neoplasms; General Surgery; Humans; Incidence; Interferon-alpha; Male; Neoplasm Metastasis; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Risk Assessment; Sirolimus; Somatostatin; Survival Analysis; Treatment Outcome

Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression of HCC.. MHCC97H cells were used as targets to explore the effect of sirolimus on cell cycle progression, apoptosis, proliferation, and its antiangiogenic mechanism. LCI-D20, a highly metastatic model of human HCC in nude mice, was also used as the model tumor to explore the effect of sirolimus on tumor growth and metastatic progression.. In vitro, sirolimus induced cell cycle arrest at the G1 checkpoint and blocked proliferation of MHCC97H cells but did not induce apoptosis. In vivo, sirolimus prevented tumor growth and metastatic progression in LCI-D20. Intratumoral microvessel density and circulating levels of VEGF in tumor-bearing mice were also significantly reduced in sirolimus treatment group. Quantitative RT-PCR showed that sirolimus down-regulated the mRNA expression of VEGF and HIF-1a, but not of bFGF, and TGF-b in MHCC97H cells. Furthermore, western blot analysis confirmed that sirolimus also decreased expression of HIF-1a at protein level, in parallel with the down-regulation of the levels of VEGF protein excretion in a time-dependent manner as compared to untreated control cells following anoxia.. The immunosuppressive macrolide sirolimus prevents the growth and metastatic progression of HCC, and suppresses VEGF synthesis and secretion by downregulating HIF-1a expression. Sirolimus may be useful for clinical application in patients who received a liver transplant for HCC.

Topics: Actins; Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Division; Cell Line, Tumor; DNA Primers; Fibroblast Growth Factor 2; Humans; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; RNA, Messenger; Sirolimus; Transforming Growth Factor beta; Transplantation, Heterologous; Vascular Endothelial Growth Factor A

Retinoic acid presently is the most advanced agent able to improve the efficacy of radioiodine therapy in differentiated thyroid carcinoma. In order to identify compounds with higher efficacy a panel of pharmacologically well-characterized compounds with antitumour action in solid cancer cell lines was screened.. The effects of the compounds on iodide uptake, cell number, proliferation and apoptosis were evaluated.. In general, compounds were more effective in cell lines derived from more aggressive tumours. The effectiveness in terms of number of responsive cell lines and maximal increase in iodide uptake achieved decreased in the order: APHA > valproic acid approximately sirolimus approximately arsenic trioxide > retinoic acid approximately lovastatin > apicidine approximately azacytidine approximately retinol approximately rosiglitazone approximately bortezomib.. We hypothesize that testing of cells from primary tumours or metastases in patients may be a way to identify compounds with optimum therapeutic efficacy for individualized treatment.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Boronic Acids; Bortezomib; Carcinoma; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Iodides; Lovastatin; Neoplasm Metastasis; Oxides; Pyrazines; Sirolimus; Thymus Gland; Thyroid Neoplasms; Tretinoin

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

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

To test the effect of rapamycin (RAPA) on hepatic tumor growth and metastasis in Sprague-Dawley (SD) rat model and explore the possible mechanism.. SD rat hepatocellular carcinoma (HCC) model with metastatic potential was induced by diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR). 120 SD rats were randomized into four groups 16 weeks after DEN and NMOR treatment, and received 4-week intraperitoneal injection of RAPA (1.5 or 4.5 mg x kg(-1) x d(-1)), CsA (25 mg x kg(-1) x d(-1)) or equal volume of 0.9% saline, respectively. Tumor growth and metastasis were checked after the 4-week treatment. Serum vascular endothelial growth factor (VEGF) was determined by enzyme-linked immunosorbent assay (ELISA). Antiangiogenetic effects were assessed by CD34 immunostaining. The levels of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and VEGF proteins and mRNAs were detected by immunohistochemistry, western blot and reverse transcriptase-polymerase chain reaction (RT-PCR).. The mean liver weight (5.58% +/- 0.42% and 5.69% +/- 0.74%), the metastatic liver nodules (5.12 +/- 0.68 and 5.67 +/-1.12), the metastasis lung nodules (0.43 +/- 0.11 and 0.45 +/- 0.83), and the lung metastasis rate (17.2% and 14.8%) were lower in rats treated with RAPA 1.5 mg x kg(-1) x d(-1) or 4.5 mg x kg(-1) x d(-1) than those in rats treated with saline, which were 10.42% +/- 1.86%, 12.36 +/- 3.45, 1.81 +/- 0.3 and 50.0% respectively (P < 0.01 or P < 0.05). The intratumoral microvessel density (MVD), serum VEGF, and the levels of HIF-1 alpha and VEGF were lower in RAPA-treated rats than those in control rats. However, CsA-treated rats showed an opposite trend compared with the RAPA-treated rats.. RAPA can repress the expression of angiogenesis-promoting factors HIF-1 alpha and VEGF, and significantly inhibits the growth and metastasis of HCC.

Topics: Animals; Carcinoma, Hepatocellular; Cyclosporine; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Immunosuppressive Agents; Liver Neoplasms, Experimental; Male; Microvessels; Neoplasm Metastasis; Neovascularization, Pathologic; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; Vascular Endothelial Growth Factors

Hepatocellular carcinoma (HCC) represents one of the most common malignancies globally, accounting for nearly one million new cases per year. Although the treatment of extrahepatic metastases from primary liver tumors is essentially palliative, a solitary metastasis from such tumors offers a possibility of cure by surgical resection. The adrenal gland is an uncommon site for metastasis from primary liver tumors.. We report a liver transplantation case of HCC and hepatitis B virus in a 23-year-old man with an excellent postoperative result. However, because an increased alpha-fetoprotein was evident and complete radiologic and blood tests were performed, all of which were normal. Three years posttransplantation, a right adrenal mass was identified by CT. PAAF was performed as well as adrenalectomy for a solitary adrenal metastasis from hepatocellular carcinoma.. The patient underwent adrenalectomy for the right adrenal metastasis at 3 years following liver transplantation for HCC. He is presently alive and disease-free 24 months after adrenalectomy.. Carefully selected patients with solitary metastasis from HCC may be considered for resection.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adult; Carcinoma, Hepatocellular; Everolimus; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Neoplasm Metastasis; Sirolimus; Survival Analysis; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Melanoma is highly resistant to chemotherapy. In melanoma, the PI3K-AKT-mTOR signaling pathway is constitutively activated through multiple mechanisms. Several experimental studies suggest that targeting the PI3K-AKT-mTOR signaling pathway is a promising strategy to overcome chemoresistance. This is the first report describing a chemosensitizing effect of mTOR inhibition in patients with melanoma. We report two cases of patients with metastatic melanoma who showed significant remission after combination of carboplatin and paclitaxel with the mTOR inhibitor sirolimus. Our case report, together with the literature discussed, suggests that mTOR inhibition possibly enhances the sensitivity of melanoma cells to chemotherapy and should prompt in-depth and clinical investigation.

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Drug Delivery Systems; Female; Humans; Melanoma; Neoplasm Metastasis; Paclitaxel; Protein Kinases; Signal Transduction; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

The interaction of cancer cells with extracellular matrix (ECM) is important in metastasization. Here we identified the molecules of the ECM expressed by sarcomatous malignant mesothelioma, and their effect on adhesion and spreading. In addition, by analyzing the relationship between translation and attachment to matrix, we found that mesothelioma cells rely on continuing translation to efficiently attach to matrix, and rapamycin inhibition affects spreading and migration of cancer cells. Specifically, we found that sarcomatous cells produce high amounts of fibronectin, able to support the spreading of mesothelioma cells. Spreading of cancer cells on fibronectin does not require de novo transcription but is sensitive to cycloheximide, an inhibitor of protein synthesis. Next, we analyzed the involvement of the mammalian target of rapamycin (mTOR) pathway, a major pathway controlling translation. Cancer cells have a constitutively active mTOR pathway; surprisingly, inhibition of mTOR complex 1 (mTORC1) by rapamycin barely affects the global rate of translation and of initiation of translation, but deeply inhibits mesothelioma spreading on ECM. The effects of rapamycin and cycloheximide on spreading were observed in several mesothelioma cell lines, although with different magnitude. Overall, data suggest that adhesion and spreading of mesothelioma cells on ECM require the translation of pre-synthesized mRNAs, and mTORC1 activity. We speculate that mTORC1 activity is required either for the translation of specific mRNAs or for the direct modulation of cytoskeletal remodeling.

Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Culture Media, Serum-Free; Cycloheximide; Fibronectins; Humans; Lung Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mesothelioma; Multiprotein Complexes; Neoplasm Metastasis; Protein Biosynthesis; Protein Synthesis Inhibitors; Proteins; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

The clinical use of immunotoxins (ITs) has been hampered by hepatotoxicity, and the induction of a strong human-anti-IT response. The human-anti-IT response results in neutralisation of the immunoconjugates, rendering repetitive treatment inefficacious.. We evaluated the combination of cyclosporin A (CsA) with various Pseudomonas exotoxin A-based ITs in human breast, cervical, and prostate cancer cell lines measured by protein synthesis, cell viability, and TUNEL assay. Furthermore, expression of essential proteins were analysed by western blot. We used cervical cancer model in nude rats to evaluate the anti-metastatic effect of the combination. The anti-immunogenic response by the CsA treatment was investigated in immunocompetent rats.. The combination of CsA with ITs caused remarkable synergistic cytotoxicity, in several cancer cell lines, characterised by protein synthesis inhibition, decreased cell viability, and an increased apoptotic index. Furthermore, the combination strongly inhibited formation of metastases in a cervical cancer model in nude rats with a statistically significant increase in median survival time of the combination-treated animals, as compared with those receiving a suboptimal dose of IT alone. Notably, we found in immunocompetent rats that the anti-IT immunoresponse elicited by repeated administration of IT was efficiently abrogated by CsA; notably the antibody responds towards the highly immunogenic PE was shown to be prevented.. The combination of ITs and CsA might constitute a significant improvement in the clinical potential of systemic IT treatment of cancer patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cyclosporine; Drug Synergism; Female; Humans; Immunotoxins; Male; Neoplasm Metastasis; Neoplasms, Experimental; Rats; Sirolimus; Tacrolimus

Topics: Antineoplastic Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Models, Biological; Neoplasm Metastasis; Phosphorylation; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Urinary Bladder Neoplasms

The mammalian target of rapamycin (mTOR) is implicated in cell growth especially during cancer development and progression. Its action is dependent on well known oncogenic pathways that regulate tumor cell growth and cell cycle progression, in response to different stimuli. Sirolimus, temsirolimus and everolimus are specific inhibitors of mTOR that have originally been characterized by their antifungal and immunosuppressive properties, but also significantly inhibit cancer cells'proliferation, invasion, and metastasis, and promote apoptosis. In addition, mTOR inhibitors display potent antiangiogenic properties by the suppression of vascular endothelial growth factor signal transduction. The antitumoral effects of mTOR inhibitors, as a monotherapy or in combination with tyrosine kinase inhibitors or usual cytotoxic agents, have been extensively suggested in preclinical studies, including animal models. In a clinical setting, preliminary reports have demonstrated that mTOR inhibitors use is associated with an acceptable safety profile. Currently, mTOR inhibitors are tested in multiple trials and various cancer types, usually in intermittent schedules to avoid significant immunosuppression. Of particular interest is the use of mTOR inhibitors in the field of organ transplantation, including liver transplantation, in preventive or curative strategies, for the treatment of recurrent hepatocellular carcinoma and de novo post-transplantation malignancies.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Everolimus; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Liver Transplantation; Neoplasm Invasiveness; Neoplasm Metastasis; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

Topics: 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

Sirolimus (SRL) acts as a primary immunosuppressant or antitumor agent. The aim of the present study was to evaluate the influence of SRL on the recurrence rate and survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) exceeding the Milan criteria.. We retrospectively examined 73 consecutive patients who underwent OLT for HCC exceeding the Milan criteria from March 2004 through December 2005. Among them, 27 patients were treated with SRL-based immunosuppressive protocols after OLT, and 46 patients by an FK506-based protocol. Statistical analysis was based on the intent-to-treat method.. The 2 groups were comparable in all clinicopathologic parameters. The mean overall survival was 594 +/- 35 days in the SRL group and 480 +/- 42 days in the FK506 group (P = .011); the mean disease-free survival period was 519 +/- 43 days in the SRL group and 477 +/- 48 days in the FK506 group (P = .234). Multivariate analysis revealed Child's status (P = .004) and immunosuppressive protocol (P = .015) were the significant factors affecting overall survival. Only microvascular invasion (P = .004) was significantly associated with disease-free survival. Among 24 surviving patient in the SRL group, 2 patients had SRL discontinued for toxicity; 10 had SRL monotherapy immunosuppression.. The SRL-based immunosuppressive protocol improved the overall survival of patients after OLT for HCC exceeding the Milan criteria, probably by postponing recurrence and with better tolerability.

Topics: Adolescent; Adult; Carcinoma, Hepatocellular; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Patient Selection; Retrospective Studies; Sirolimus; Survival Analysis; Survivors; Tacrolimus

(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: Adult; Carcinoma; Carcinoma, Squamous Cell; Fatal Outcome; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphangitis; Male; Neoplasm Metastasis; Reoperation; Sirolimus; Skin Neoplasms

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

We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model of human glioma. Here, we show that myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. Intratumoral injection of live myxoma virus when compared with control inactivated virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models [D341 median survival: 21 versus 12.5 days; P = 0.0008; Daoy median survival: not reached (three of five mice apparently "cured" after 223 days) versus 75 days; P = 0.0021]. Rapamycin increased the extent of viral oncolysis, "curing" most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice (median survival of mice treated with live virus (LV) and rapamycin, versus LV alone, versus rapamycin alone, versus inactivated virus: 25 days versus 19, 13, and 11 days, respectively; P < 0.0001). Rapamycin increased the levels of constitutively activated Akt in Daoy and D341 cells, which may explain its ability to enhance myxoma virus oncolysis. These observations suggest that myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.

Topics: Animals; Antibiotics, Antineoplastic; Combined Modality Therapy; Enzyme Activation; Humans; Injections, Intralesional; Medulloblastoma; Mice; Mice, Nude; Myxoma virus; Neoplasm Metastasis; NIH 3T3 Cells; Oncogene Protein v-akt; Oncolytic Virotherapy; Sirolimus; Virus Replication; Xenograft Model Antitumor Assays

To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapamune, rapamycin) in a consecutive cohort of 248 liver allograft recipients.. Thirty-six liver transplant patients with hepatocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n = 18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT.. The patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT. Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo posttransplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable.. The conversion to SRL-based immunosuppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.

Topics: Adaptor Proteins, Signal Transducing; Adult; Calcineurin; Carcinoma, Hepatocellular; Female; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phosphoproteins; Renal Insufficiency; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation; Transplantation, Homologous

To investigate the effects of rapamycin (RPM) in inhibiting the growth and metastasis of hepatocellular carcinoma (HCC).. Human HCC cells of the line MHCC97H with a high potential of metastasis were divided into 3 groups to be cultured with cyclosporine A (CsA) 100 ng/ml, RPM 10 ng/ml, or CsA + RPM for 48 hours. Flow cytometry was used to examine the apoptosis and cell cycle MTT method was used to examine the effect of RMP on the proliferation of the MHCC97H cells. RT-PCR was used to detect the mRNA expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hypoxia-inducible factor-1alpha (HIF-1alpha), and transforming growth factor b (TGFb). Another MHCC97H cells were cultured in complete medium without RPM for 48 hours, then the protein expression of VEGF in the supernatant was detected by ELISA. Twenty-eight nude LCI-D20 mice were inoculated with human HCC cells and then divided into 4 groups to be fed with CsA (25 mg/kg), RPM (2 mg/kg), CsA + RPM, and normal saline (0.2 ml, as control group) for 35 days. Then the mice were killed to take the weight of inoculated tumor, measure the blood drug concentration, calculate the lung metastasis rate and number of metastatic foci, and observe pathology of the lung.. CsA showed no effect on the cycle of the MHCC97H cells. The MHCC97H cells of the RPM and CsA + RPM groups arrested at the stage G(0)/G(1) (both P = 0.000). MMT method also showed that the proliferation of the MHCC97H cells in the RPM and CsA + RPM groups were blocked (P = 0.003 and P = 0.002). However, CsA did not influence the proliferation of the MHCC97H cells. Flow cytometry showed that RPM did not promote the apoptosis of the MHCC97H cells. RT-PCR showed that RPM down-regulated the mRNA expression of VEGF and HIF-1alpha (both P < 0.05), however, did not influence the mRNA expression of bFGF, TGFb, and TGFb. The VEGF protein level in the supernatant of the culture fluid of MHCC97H cells of the RPM group was (890.3 +/- 25.1) pg/ml, significantly lower than that of the control group, (1583.7 +/- 17.3) pg/ml (P = 0.000). The tumor inhibiting rate of the RPM group was 63.7%, not significantly different from that of the RPM + CsA group (80.9%, P = 1.000). The metastatic rate of the CsA and control groups were both 100% with a higher number of metastatic tumors in the CsA group (P = 0.046).. RPM significantly inhibits the growth and metastasis of HCC. RPM-based immunosuppressive regimen may be of value in HCC patients receiving liver transplantation.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Enzyme-Linked Immunosorbent Assay; Fibroblast Growth Factor 2; Flow Cytometry; Humans; Immunosuppressive Agents; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Non-small cell lung cancer (NSCLC) expresses a particularly aggressive metastatic phenotype, and patients with this disease have a poor prognosis. CXC chemokine receptor 4 (CXCR4) is a cell surface receptor that has been shown to mediate the metastasis of many solid tumors including lung, breast, kidney, and prostate. In addition, overexpression of the epidermal growth factor receptor (EGFR) is associated with the majority of NSCLC and has been implicated in the process of malignant transformation by promoting cell proliferation, cell survival, and motility. Here we show for the first time that activation of the EGFR by EGF increases CXCR4 expression and the migratory capacity of NSCLC cells. Furthermore, many solid tumors are associated with low oxygen tension, and when NSCLC cells were cultured with EGF under hypoxic conditions, CXCR4 expression was dramatically enhanced. A molecular analysis of these events indicated that augmented CXCR4 expression was regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signal transduction pathway, activation of hypoxia inducible factor (HIF) 1alpha, and ultimately HIF-1-dependent transcription of the CXCR4 gene. Thus, a combination of low oxygen tension and overexpression of EGFR within the primary tumor of NSCLC may provide the microenvironmental signals necessary to upregulate CXCR4 expression and promote metastasis.

Topics: Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Separation; Cell Survival; Chemokine CXCL12; Chemokines, CXC; Chemotaxis; Dose-Response Relationship, Drug; Epidermal Growth Factor; Flow Cytometry; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Neoplasm Metastasis; Oxygen; Phosphatidylinositol 3-Kinases; Phosphoric Monoester Hydrolases; Promoter Regions, Genetic; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptors, CXCR4; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Tumor Suppressor Proteins; Up-Regulation

Topics: Adult; Female; Humans; Immunosuppression Therapy; Liver Neoplasms; Liver Transplantation; Lung Neoplasms; Mycophenolic Acid; Neoplasm Metastasis; Sirolimus; Tomography Scanners, X-Ray Computed; White People

We used an experimental in vitro model of human ovarian surface epithelium (OSE), the tissue of origin of >90% of ovarian cancers, to more precisely define the contribution of hepatocyte growth factor (HGF) to various OSE phenotypes at different stages of neoplastic progression. Neoplastic transformation of OSE in cultures was achieved by multiple genetic manipulations, resulting in the nontumorigenic line IOSE-29, the tumorigenic IOSE-Ov29, and the tumor-derived, more highly malignant IOSE-Ov29/T4. We demonstrate here that, compared to IOSE-29, IOSE-Ov29 and IOSE-Ov29/T4 exhibited higher levels of the HGF receptor Met and an increasing duration of ERK1/2 activation with malignant progression, in conjunction with other neoplastic properties. HGF activated Met signaling in all lines but elicited different responses: HGF induced cell dispersion (scattering) and collagen gel invasion in IOSE-Ov29 and IOSE-Ov29/T4 but did not alter the growth pattern of IOSE-29. Inhibition with PD98059 and LY294002 independently prevented HGF-induced invasive growth. Furthermore, our results show that HGF-induced invasion can be mediated through a rapamycin-sensitive p70 S6K cascade, which demonstrates that p70S6K can regulate cell motility in addition to its well-established role in protein synthesis. Taken together, our data correlate specific responses to HGF-mediated signaling with specific signaling pathways and with progressive neoplastic changes.

Topics: Carcinoma; Cell Line, Transformed; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Enzyme Inhibitors; Epithelial Cells; Female; Hepatocyte Growth Factor; Humans; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Ovary; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Receptors, Growth Factor; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus

Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Endothelial Growth Factors; Lymphokines; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neovascularization, Pathologic; Sirolimus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Epstein-Barr Virus Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Mice; Neoplasm Metastasis; Postoperative Complications; Sirolimus; Transplantation Immunology; Tumor Virus Infections; Virus Activation