Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.
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PMID:Drug insight: advances in renal cell carcinoma and the role of targeted therapies. 1765 52

Temsirolimus is a novel inhibitor of the mammalian target of rapamycin, with antitumor activity in advanced tumors. Because temsirolimus and its metabolite, sirolimus, are cytochrome P450 (CYP) 3A4/5 substrates, the potential exists for interaction with drugs that induce CYP3A activity, including enzyme inducers and rifampin. Cancer patients received once-weekly intravenous (IV) 220 mg/m(2) temsirolimus with or without enzyme inducers. Coadministration with enzyme inducers decreased temsirolimus maximum plasma concentration (C(max)) by 36% and increased volume of distribution by 99%. Sirolimus C(max) and area under the concentration-time curve (AUC) were decreased by 67% and 43%, respectively. In healthy adult subjects, coadministration of 25-mg intravenous temsirolimus with rifampin had no significant effect on temsirolimus C(max) and AUC but decreased sirolimus C(max) and AUC by 65% and 56%, respectively. Rifampin decreased AUC(sum) by 41%. Temsirolimus was well tolerated in both studies. If concomitant agents with CYP3A induction potential are used, higher temsirolimus doses may be needed to achieve adequate tumor tissue drug levels.
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PMID:Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome p450-inducing medications. 1791 96

Temsirolimus (CCI-779), a small molecule inhibitor of mTOR protein, is a water-soluble synthetic rapamycin ester that has been developed in both oral and intravenous (i.v.) formulations. PI3k/Akt/mTOR pathway activation is implicated in the pathogenesis of many cancers. Inhibition of mTOR protein abrogates pathway-mediated cellular transcription and translation, leading to cell cycle arrest, antiangiogenesis and apoptosis. The drug has significant in vitro antitumor effect against a number of cancer cell lines and has demonstrated in vivo cytostatic activity in xenograft models. Flat dosing of 25 mg, 75 mg and 250 mg i.v. weekly were selected for tumor-specific phase I trials. Biological activity was observed at all these doses. However, the frequency and intensity of the toxicities increased at higher doses and more high-dose patients had to reduce the dose or discontinue the drug. Notable temsirolimus-related toxicities include rash, mucostomatitis, diarrhea, hyperlipidemia, hyperglycemia and thrombocytopenia. Temsirolimus is farther along in clinical development than any other mTOR inhibitor in its class and has demonstrated significant activity in patients with poor-risk clear-cell renal cell carcinoma. Patients receiving temsirolimus alone achieved longer survival than those receiving interferon alone or temsirolimus plus interferon in a randomized phase III trial. Predictive biomarkers for clinical efficacy are undetermined and remain under investigation.
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PMID:Temsirolimus. 1798 19

Renal cell carcinoma (RCC) affects 38,000 individuals in the U.S. yearly. Seventy-five percent of cases are clear-cell carcinomas, and a majority is driven by dysfunction of the von Hippel-Lindau (VHL) gene. VHL loss of function and other non-VHL pathways leading to RCC share aberrant activation of the hypoxic response, such as upregulation of vascular endothelial growth factor (VEGF) and consequent neoangiogenesis. Metastatic RCC has been notoriously resistant to therapy. For decades, its treatment has been based on nephrectomy and limited use of toxic and often inefficient immunotherapy with interleukin-2 or interferon-alpha. However, new biologic agents are beginning to break the resistance barrier. Small-molecule multikinase inhibitors that target VEGF receptors (sunitinib and sorafenib) have a favorable toxicity profile and can prolong time to progression and preserve quality of life when used in newly diagnosed or previously treated patients. The anti-VEGF antibody bevacizumab enhances the response rate and prolongs disease control when added to interferon-alpha. Temsirolimus, a mammalian target of rapamycin inhibitor, prolongs the survival duration of patients with poor-risk disease. Despite three new drugs being approved for RCC in the past 2 years, responses are mostly partial and of limited duration. Multiple new drugs and drug combinations are undergoing clinical trials and will likely impact the treatment of RCC in future years. Compounds found to be active in the metastatic setting are now being tried in earlier stage disease in an attempt to improve curability. However, no method has yet been validated to predict patient response to these newer treatments.
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PMID:Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies. 1816 17

Temsirolimus, an ester of sirolimus (rapamycin), selectively inhibits the kinase mammalian target of rapamycin and consequently blocks the translation of cell cycle regulatory proteins and prevents the over expression of angiogenic growth factors. Patients with advanced renal cell carcinoma and a poor prognosis who received a once-weekly intravenous infusion of temsirolimus 25 mg experienced significant survival benefits compared with patients receiving standard interferon-alpha (IFNalpha) therapy (3-18 MU subcutaneously three times weekly) in a large phase III clinical study. Median overall survival was 10.9 versus 7.3 months, progression-free survival was 5.5 versus 3.1 months. Objective response rates were 8.6% in temsirolimus recipients versus 4.8% in IFNalpha recipients. Temsirolimus monotherapy recipients experienced significantly fewer grade 3 or 4 adverse events and had numerically fewer withdrawals for adverse events than patients receiving IFNalpha.
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PMID:Temsirolimus: in advanced renal cell carcinoma. 1837 Apr 42

HER-2 is a tyrosine kinase receptor which is overexpressed in 20-25% of breast cancer patients and is associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody directed against the HER-2 receptor, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in metastatic patients, as well as halving the recurrence rate and improving survival in early breast cancer. Even with these impressive results, the reality is that not all patients will benefit form this therapy, and in those who do, resistance to trastuzumab can often develop within 1 year of treatment initiation. Beyond trastuzumab therapy, a "second wave" of monoclonal antibodies and tyrosine kinase inhibitors has emerged. These drugs have variable properties including: 1) dual inhibition against EGFR and HER-2, such as lapatinib, HKI-272 and pertuzumab; 2) anti-angiogenesis such as bevacizumab and pazopanib; 3) anti-mTOR action such as Temsirolimus; and 4) anti-Hsp90 such as 17-AAG. When used in combination with trastuzumab, or with cytotoxic chemotherapy, or as single agents, these new anti-HER-2 strategies bear the potential of arresting the tumorigenesis process. In this article, we present the current strategies in the treatment of breast cancer patients who overexpress HER-2, with particular focus on new tyrosine kinase inhibitors that can be used in combination with or after trastuzumab therapy.
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PMID:HER-2 positive breast cancer: what else beyond trastuzumab-based therapy? 1853 32

The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein translation, cell growth, and apoptosis. Recently, there has been an enormous increase in our understanding on molecular mechanisms underlying the therapeutics of rapamycin in cancer. Alterations in the pathway regulating mTOR occur in many solid malignancies including prostate, bladder, and kidney cancer; in vitro and in vivo models of prostate and bladder cancer have established the importance of the mTOR pathway in control of cancer progression and metastasis. Temsirolimus (Torisel) and everolimus (RAD-001), two ester analogues of rapamycin, as well as rapamycin itself have clear antitumor activity in in vitro and in vivo models and are under clinical trial investigations for prostate and bladder cancer. Phase II and III trials have already established the clinical efficacy of temsirolimus in renal cancer, and current renal trials are evaluating the combined effects of vascular endothelial growth factor and mTOR inhibition. Ongoing studies in prostate and bladder cancer will soon define the activity and safety profiles of everolimus and temsirolimus. Recent molecular advances have uncovered a startling complexity in the macromolecular function of mTOR complexes, with the identification of new mTOR partners (raptor, rictor, FKBP38, PRAS40, and mSIN1), putative cancer therapeutic/prognostic targets for future clinical trials.
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PMID:Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. 1856 9

Temsirolimus is a specific inhibitor of mammalian target of rapamycin (mTOR) that is approved for the treatment of advanced renal cell carcinoma. mTOR is unique among antitumor drug targets because it is a convergence point for many signaling pathways. Activation of mTOR by various growth signals increases the synthesis of proteins needed for cell-cycle progression and tumor growth. Temsirolimus demonstrates a significant improvement in overall survival in patients with advanced renal cell carcinoma and poor-prognostic features, thereby validating the importance of mTOR in the natural history of this disease. mTOR might also be an important target in other tumor types, and more than 100 ongoing clinical trials are designed to identify additional malignancies that respond to temsirolimus and other mTOR inhibitors, either alone or in combination with other targeted agents or chemotherapy.
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PMID:Mechanisms of Disease: survival benefit of temsirolimus validates a role for mTOR in the management of advanced RCC. 1860 93

Temsirolimus is a targeted therapy that inhibits mammalian target of rapamycin (mTOR), a central regulator of tumor cell responses to growth stimuli. Temsirolimus has a broad anticancer activity profile that impacts tumor cell growth, proliferation, and survival through its specific inhibition of mTOR. In a randomized phase III trial that enrolled previously untreated patients with advanced renal cell carcinoma (RCC) and poor prognostic features, temsirolimus significantly prolonged overall survival compared with interferon-alpha, a standard therapy (p = 0.008). Because of the results, temsirolimus was approved by the U. S. Food and Drug Administration for treatment and is considered a first-line treatment for patients with advanced RCC with poor prognostic features. Temsirolimus is administered at a flat weekly IV dose of 25 mg given over 30-60 minutes. Gastrointestinal disorders (stomatitis, anorexia, nausea, diarrhea, and vomiting), rash, fatigue, edema, infections, and dyspnea, as well as hematologic and metabolic laboratory abnormalities occur in patients receiving temsirolimus. Metabolic side effects include hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and hypophosphatemia. Most adverse reactions associated with temsirolimus can be managed medically or addressed by supportive measures. Nurses can improve patient outcomes through early recognition of side effects and prompt interventions.
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PMID:Temsirolimus, an mTOR inhibitor for treatment of patients with advanced renal cell carcinoma. 1867 30

Renal cell carcinoma has made considerable progress in the past years, and new emerging strategies are coming almost every year since 2005. Development of targeted therapies in renal cell cancer is largely due to the fact that Von Hippel Lindau gene is often mutated in sporadic renal cell cancer. Von Hippel Lindau protein abnormalities lead to accumulation of hypoxia inducible factor-alpha, and activation of a series of gene, including vascular endothelial growth factor, and thus induce angiogenesis. Results from many recent studies with new agents, blocking the vascular endothelial growth factor pathway or the mammalian target of rapamycin pathway, have been recently reported and offer new strategic options for the patients with metastatic renal cell carcinoma. Sunitinib, sorafenib, and combination of bevacizumab and interferon improves progression free survival in either first or second line treatment of renal cell cancer and have been approved. Temsirolimus, a mammalian target of rapamycin inhibitor regulating hypoxia inducible factor-alpha, improves survival in renal cancer with poor risk features. Finally, everolimus improves progression free survival in patients who fail tyrosine kinase inhibitors. Overall, treatment of metastatic renal cell carcinoma is currently moving from the cytokine era to the targeted agent era. However, many questions still remain on the efficacy of combination treatments and on the best way to get complete remission, which is probably the best way to lead to cure of metastatic renal cell cancer in the future.
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PMID:Signaling inhibitors in metastatic renal cell carcinoma. 1883 38


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