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)

CCI-779 (temsirolimus), an ester of rapamycin and an inhibitor of the mammalian target of rapamycin (mTOR), is currently in phase II trials for treatment of patients with solid cancers. The mTOR functions as a checkpoint for cell proliferation, with upstream Akt and downstream p70S6K serving as its most important mediators. The aim of this study was to evaluate the expression and activation of the Akt-mTOR-p70S6K pathway in renal cell carcinoma (RCC), seeking to strengthen the rationale for targeted therapy of RCC using rapamycin or a rapamycin analogue. Tissue microarray sections containing 128 primary RCCs, 22 metastatic RCCs, and 24 non-neoplastic (normal) kidneys (NK) were immunostained with monoclonal antibodies to phosphorylated (p)-Akt (Ser473), p-mTOR (Ser2448), and p-p70S6K (Thr389). Western blotting was performed on 3 cases of clear cell RCC (CRCC) and the corresponding non-neoplastic (normal) renal tissues using the same antibodies. The immunostain scoring system included: (a) location; (b) distribution; and (c) intensity. The normal kidneys provided baseline scores for comparison. Expression of p-Akt, p-mTOR, and p-p70S6K was seen in 100% (n = 24) of NKs and nearly 100% (n = 150) of both primary and metastatic RCCs. The p-p70S6K was located in the nucleus in both NKs and RCCs. The p-Akt was observed in the nucleus and cytoplasm of NKs and in the nucleus and cytoplasm/ membrane (plasmalemma) of RCCs. The p-mTOR was identified in the membrane of NKs and the membrane/nucleus of RCCs. The levels of expression of p-p70S6K, p-mTOR, and p-Akt were significantly higher in RCC than in NK in the overall pattern (intensity and distribution, p <0.05). Western blotting also showed higher expression of p-p70S6K, p-mTOR, and p-Akt in RCCs compared to the corresponding normal kidney tissues (p <0.05). These findings indicate that correlative over-expression and activation of p-Akt, p-mTOR, and p-p70S6K are commonly observed in RCCs. After considering these findings in the context of other established protein circuitries and pathways in RCC, we propose therapeutic approaches that incorporate rapamycin-like agents and other small molecule inhibitors in a combinatorial fashion in future clinical trials for RCC.
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PMID:Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal cell carcinomas. 1695 Dec 69

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In the case of metastatic disease at presentation, a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment. Interferon (IFN)-a offers in a small but significant percentage of patients advantage in overall survival. Interleukin (IL)-2-based therapy gives similar survival rates. To date, hormonal therapy and chemotherapy do not have a proven impact on survival. Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel-Lindau (VHL) gene. This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor (VEGF) in this highly vascularized tumor. This opens interesting new treatment strategies including blockade of VEGF with the monoclonal antibody bevacizumab (Avastin) and inhibition of VEGF receptor tyrosine kinases with small oral molecules such as sunitinib (SU11248, Sutent) or PTK787. Likewise, inhibition of the Raf kinase pathway with oral sorafenib (Bay 43-9006, Nexavar) or inhibition of the mTOR pathway with intravenous CCI-779 are under investigation. Preliminary clinical results with all these compounds are promising, and the results of ongoing first-line phase III studies will become available in the next years.
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PMID:Targeted approaches for treating advanced clear cell renal carcinoma. 1697 18

Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. Alterations in the mTOR signaling pathway can lead to neoplastic transformation and progression. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. Thus, mTOR is a promising target for the treatment of human malignancies. Rapamycin and its analogues, including temsirolimus, everolimus, and AP23573, block the mTOR signaling pathway and induce a cellular state akin to starvation, with significant antitumor activity in a variety of malignancies, including renal cell carcinoma (RCC). Current data from ongoing clinical trials suggest that mTOR-targeted therapy with rapamycin derivatives is well tolerated with significant clinical activity in patients with advanced-stage RCC. Specifically, temsirolimus as monotherapy has demonstrated improved progression-free and overall survival in patients with poor-risk advanced-stage RCC. Everolimus has also demonstrated promising antitumor activity in patients with metastatic RCC. However, optimal dose, treatment schedule, selection of patients, and appropriate combination strategies with other novel agents need to be defined for mTOR-targeted therapies in the treatment of advanced-stage RCC.
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PMID:Current data with mammalian target of rapamycin inhibitors in advanced-stage renal cell carcinoma. 1702 98

The VHL tumor-suppressor gene is mutated or silenced in most clear cell renal carcinomas (RCCs). pVHL loss results in the stabilization of the heterodimeric transcription factor hypoxia-inducible factor (HIF) and enhanced transactivation of HIF target genes. Downregulation of HIF is both necessary and sufficient for pVHL to suppress the growth of human renal carcinoma cells in preclinical models. HIF itself has been difficult to inhibit with drug-like molecules although a number of agents that indirectly inhibit HIF, including mammalian target of rapamycin (mTOR) inhibitors, have been identified. Moreover, a number of drugs have been developed that target HIF-responsive gene products, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), implicated in tumorigenesis. Many of these targeted therapies have demonstrated significant activity in kidney cancer clinical trials and represent substantive advances in the treatment of this disease. How these agents should be combined with one another and with conventional agents is the subject of current trials.
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PMID:Molecular pathways in renal cell carcinoma--rationale for targeted treatment. 1704 88

Significant achievements in the basic sciences have led to a greater knowledge of the underlying signaling pathways in renal cell cancer (RCC), including the mammalian target of rapamycin (mTOR) pathway (phosphoinositide 3-kinase/Akt pathway). The mTOR pathway has a central role in the regulation of cell growth and increasing evidence suggests its dysregulation in cancer. Receiving input from multiple signals, including growth factors, hormones, nutrients, and other stimulants or mitogens, the pathway stimulates protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase. The mTOR pathway also contributes to many other critical cellular functions, including protein degradation and angiogenesis. Hence, use of inhibitors of the pathway represents a new strategy for the targeted treatment of RCC, and mTOR inhibitors have already shown promising clinical efficacy and low toxicity profiles in unselected patients with metastatic RCC. As with other new, targeted cancer agents, the future use of mTOR inhibitors will benefit from reproducible biomarkers that can be used in the clinic to identify patients most likely to respond and to document modulation of the drug target in addition to clinical response.
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PMID:Mammalian target of rapamycin inhibitors in renal cell carcinoma: current status and future applications. 1704 90

Recent developments in molecular biology have lead to an increased understanding of the events involved in renal cell carcinoma (RCC) carcinogenesis. In this field, basic molecular pathways important to oncogenic transformation secondary to Von Hippel-Lindau (VHL) tumor suppression gene inactivation, associated to clear-cell RCC, have been elucidated. Loss of function of VHL results in the high-expression of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). New therapies against specific targets in RCC have demonstrated significant clinical activity in patients. These therapeutic approaches are based on the VEGF inhibition by using anti-VEGF monoclonal antibodies (bevacizumab) or multi-kinase inhibitors, that also target PDGF and c-kit tyrosine kinases (sorafenib, sunitinib); or by the inhibition of the mammalian target of rapamycin (mTOR) pathway (temsirolimus). This article reviews current knowledge of molecular pathogenesis of inherited and sporadic RCC.
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PMID:Molecular biology of renal cell carcinoma. 1707 68

The understanding of cellular processes underlying tumour biology has allowed the development of novel molecular-targeted drugs with optimistic results in renal cell carcinoma (RCC). Mutations in the von Hippel-Lindau gene are found in 75% of sporadic RCCs, which results in upregulation of several genes involved in angiogenesis, e.g. vascular endothelial growth factor and platelet-derived growth factor. Other activated pathways in RCC are the epidermal growth factor receptor and the mTOR pathway, which regulate survival and cell growth. In addition to temsirolimus (an mTOR inhibitor) two different strategies have been studied to inhibit these targets: monoclonal antibodies, e.g. bevacizumab, and small molecule tyrosine-kinase inhibitors such as sorafenib, sunitinib and AG 013736. Phase II studies with these drugs reported substantial clinical activity in advanced RCC. Survival benefit was reported with temsirolimus, sunitinib and sorafenib in randomized trials, which led to the accelerated approval of sorafenib and sunitinib for advanced RCC by regulatory authorities in the USA and Europe. Nevertheless, as new therapies develop, new challenges arise for the optimum use of these targeted drugs. We discuss the rationale and the clinical development of these novel molecular-targeted agents, with special emphasis on updated information presented at recent meetings because of the relevance of the data reported and the potential future impact in the management of patients with RCC.
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PMID:Present strategies in the treatment of metastatic renal cell carcinoma: an update on molecular targeting agents. 1709 82

In the past several years, significant advances in the underlying biological mechanisms of renal cell cancer, particularly the role of tumour angiogenesis, have permitted the design of molecularly targeted therapeutics. For this review, single-agent therapies inhibiting the following different targets were identified in the published literature: epithelial growth factor receptor, vascular endothelial growth factor receptor, basic fibroblast growth factor receptor, platelet-derived growth factor, nuclear factor-kappabeta, the mammalian target of rapamycin (mTOR) pathway, raf kinase pathway and tyrosine kinase pathway. Distinct fields of clinical research have emerged--monoclonal antibodies, small molecules, nanopeptides and immunomodulators. All therapies demonstrated acceptable toxicity profiles. Clinical benefit was assessed on the basis of the reported criteria for each study, and antitumour response (regression or delay in progression-free survival) ranged from 5% to 71%. On the basis of the limited studies to date, targeted therapies offer the greatest clinical benefit in the management of this malignancy, although additional basic research is still warranted to further improve clinical outcome.
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PMID:Targeted anti-cancer therapies for renal cancer. 1713 1

Temsirolimus (CCI779), an intravenous analog of rapamycin, presents immunosuppressive properties and also antiproliferative activity. Its principal target is the mTOR serine/threonin kinase which controls the initiation of the transcription of many ARNm implicated in carcinogenesis. Breast cancers, glioblastoma and renal cell carcinoma were particularly studied with response rates from 10 to 20 %. In haematology, mantle-cell lymphoma is of particular interest because of constitutional activation of cyclin D1 (response rate of 40 %). As a whole these data define temsirolimus as a promising new drug. Current and further developments are based on its association with chemotherapy in a concomitant or sequential way.
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PMID:[Update on clinical activity of CCI779 (temsirolimus), mTOR inhibitor]. 1714 84

Immunotherapy with interleukin-2 and interferon-alpha has been the only viable option in metastatic renal cell cancer for almost two decades. In the last several years, significant advances in the understanding of the underlying biological and molecular mechanisms of renal cell carcinoma, particularly the role of tumour angiogenesis, have led to the identification of rational therapeutic targets and permitted the design of molecularly targeted therapeutics. At present, new compounds targeting specific signalling pathways are available and have successfully passed clinical testing. The use of small molecules, such as multitargeted tyrosine kinase inhibitors, the mTOR inhibitors and monoclonal antibodies, is dramatically changing the existing concepts of systemic treatment for metastatic kidney cancer.
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PMID:Kidney cancer therapy: new perspectives and avenues. 1715 3


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