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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that has been increasingly recognized as key to the regulation of cell growth and proliferation. mTOR either directly or indirectly regulates translation initiation, actin organization, tRNA synthesis, ribosome biogenesis, and many other key cell maintenance functions, including protein degradation and transcription functions. Inhibition of mTOR blocks traverse of the cell cycle from the G1 to S phase. Preclinical data show inhibition of tumor growth in a number of cell lines and xenograft models. Clinical trials are ongoing. In metastatic renal cell cancer, both tumor regression and prolonged stabilization have been noted. mTOR inhibition appears to be a key pathway that may be useful in antitumor therapy. Renal cell cancer may be particularly susceptible through both the translation inhibition pathway and pathways that enhance HIF-1alpha gene expression, a factor believed to stimulate growth in metastatic renal cell cancer. Additional clinical trials that use agents that inhibit mTOR are ongoing.
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PMID:Mammalian target of rapamycin inhibition. 1544 35

Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Multiple strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. This review aims to overview the findings of recent clinical trials and clarify the development of these compounds for use in renal cell carcinoma. The authors also aim to clarify the molecular pathways implicated in renal cell carcinoma and the clinical results in metastatic renal cell carcinoma with agents targeting these pathways. The relevant literature was reviewed concerning pathways implicated in the pathophysiology of renal cell carcinoma including pathways activated secondary to von Hippel-Lindau gene inactivation and PI-3 kinase/Akt/mammalian target of rapamycin pathway activation. Therapeutic targeting based upon underlying molecular biology in renal cell carcinoma has strong rationale. Substantial clinical activity has been reported with various agents targeting these pathways, most notably with vascular endothelial growth factor-targeted therapy. However, investigation is needed to optimally utilize these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.
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PMID:Molecularly targeted therapy in renal cell carcinoma. 1633 94

Metastatic renal cell carcinoma is resistant to current therapies. The phosphoinositide 3-kinase (PI3K)/Akt signaling cascade induces cell growth, cell transformation, and neovascularization. We evaluated whether targeting this pathway could be of therapeutic value against human renal cell carcinoma. The activation of the PI3K/Akt pathway and its role in renal cell carcinoma progression was evaluated in vitro in seven human cell lines by Western blot, cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, terminal deoxyribonucleotide transferase-mediated nick-end labeling assays, and fluorescence-activated cell sorting analysis, using two PI3K inhibitors, LY294002 and wortmannin, as well as by transfection with various Akt constructs and through Akt knockdown by small interfering RNA (siRNA). In vivo nude mice bearing human renal cell carcinoma tumor xenografts were treated with LY294002 (75 mg/kg/wk, 4 weeks, i.p.). Tumor growth was measured and tumors were subjected to Western blot and immunohistochemical analysis. Akt was constitutively activated in all cell lines. Constitutive phosphorylation of glycogen synthase kinase-3 (GSK-3) was observed in all cell lines, whereas forkhead transcription factor and mammalian target of rapamycin, although expressed, were not constitutively phosphorylated. Exposure to LY294002 or wortmannin decreased Akt activation and GSK-3 phosphorylation and reduced cell growth by up to 70% through induction of cell apoptosis. These effects were confirmed by transfection experiments with Akt constructs or Akt siRNA. Importantly, LY294002 induced up to 50% tumor regression in mice through tumor cell apoptosis. Tumor neovascularization was significantly increased by LY294002 treatment. Blood chemistries showed no adverse effects of the treatment. Our results suggest an important role of PI3K/Akt inhibitors as a potentially useful treatment for patients with renal cell carcinoma.
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PMID:The phosphoinositide 3-kinase/Akt pathway: a new target in human renal cell carcinoma therapy. 1670 36

Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but a need exists to develop more effective systemic therapies. Angiogenesis has a key role in the pathophysiology of renal cell carcinoma and vascular endothelial growth factor (VEGF) is an important mediator of this process. Sunitinib, sorafenib and axitinib are new agents which belong to a class of drugs called kinase inhibitors and inhibit the VEGF, platelet-derived growth factor (PDGF) and c-KIT receptor tyrosine kinases. Temsirolimus inhibits the mammalian target of rapamycin (mTOR). All these agents have shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients generally pretreated with immunotherapy, whilst prolonged progression-free survival in a phase 3 study has been reported with sorafenib in comparison with placebo. Further phase 3 trials are recruiting and the combination of kinase inhibitors with other therapies is under investigation.
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PMID:Kinase inhibitors in the treatment of renal cell carcinoma. 1686 Sep 97

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

The year 2006 will mark a turning point in the daily management of patients with metastatic renal cell carcinoma. The impact of immunotherapy with interferon-alpha or interleukin-2 has been shown to be restricted to a minority of patients. The growing understanding of molecular mechanisms involved in the pathogenesis of the disease, especially clear-cell carcinoma, has led to the development of multiple targeted therapies with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of the vascular endothelial growth factor receptor have been shown to improve the progression-free survival of patients in first- (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, an agent that inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.
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PMID:Targeted therapies in metastatic renal cell carcinoma: the light at the end of the tunnel. 1718 90

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remission (CR) of only 12.9%. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of RCC disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. Von Hippel-Lindau (VHL) gene inactivation is observed in most clear cell renal carcinoma, resulting in vascular endothelial growth factor (VEGF) over-expression and driving the malignant phenotype. This review discusses the efficacy of novel therapies targeting the VEGF receptor (VEGFR) (e.g. anti-VEGF antibodies, VEGFR tyrosine kinase inhibitors, mTOR inhibitors), some of which were recently approved by the Food and Drug Administration/European Medicines Evaluation Agency (FDA/EMEA) and represent the new treatment standards in RCC patients.
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PMID:Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma. 1734 Jan 58

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

Cytokine therapies have been the standard of care in metastatic renal cell carcinoma (RCC). However, these agents only provide clinical benefit to a small subset of patients and are associated with significant toxicity. A better understanding of the molecular biology of RCC has identified the vascular endothelial growth factor (VEGF) and platelet-derived growth factor signalling pathways as rational targets for anticancer therapy. The multitargeted receptor tyrosine kinase inhibitors sunitinib and sorafenib have both demonstrated improved efficacy as second-line therapy in patients with RCC. Sunitinib has also been shown to be effective in the first-line setting, and has recently received European Union approval as first-line treatment for advanced and/or metastatic RCC. There is also recent evidence that temsirolimus (an inhibitor of the mammalian target of rapamycin) and bevacizumab (a mAb targeted against VEGF) may provide benefits in the first-line treatment setting. These results confirm that inhibiting these tumour targets is a feasible approach to treatment and provides a more positive outlook for the future management of metastatic RCC.
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PMID:Treatment options in renal cell carcinoma: past, present and future. 1776 20

Metastatic renal cell cancer has traditionally been treated with interferon and interleukin-2. An improved understanding of the biology of renal cancer has engendered novel targeted therapeutic agents that have altered the natural history of this disease. The vascular endothelial growth factor and its related receptor and the mammalian target of rapamycin signal transduction pathway in particular have been utilized as therapeutic targets. Sunitinib malate, sorafenib tosylate, temsirolimus, and bevacizumab/interferon alfa have improved clinical outcomes in randomized trials. Other antiangiogenic agents have also demonstrated activity in early studies. Given the availability of multiple treatment options, several questions emerge as to how to integrate these new therapies into the management of metastatic renal cell cancer. Recently reported and planned clinical trials will help clarify the role of these agents. The future of therapy for renal cancer appears promising owing to the efficacy of these novel agents.
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PMID:Renal cell cancer. 1792 25


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