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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 clearly an important therapeutic target for advanced renal cell carcinoma (RCC), although its mechanisms of activation are not completely understood. In first-line treatment of patients who have both advanced RCC and multiple risk factors for short survival, temsirolimus improves overall survival (OS) compared with interferon. In patients whose tumors have progressed after sunitinib and/or sorafenib therapy, everolimus improves progression-free survival compared with placebo. Beyond the initial phase 3 studies demonstrating efficacy, many important questions remain in the clinical application of mTOR inhibition and in developing other inhibitors of PI3K/Akt/mTOR signaling. Important objectives of current and future clinical investigations include a more detailed description of the molecular pathology of RCC and identification of potential biomarkers that are predictive of tumor sensitivity to PI3K/Akt/mTOR targeted therapies. This information may identify other groups of RCC patients that are likely to benefit from inhibition of this signaling pathway. Additional questions concern mechanisms by which tumors become resistant to mTOR inhibitor therapy and how such resistance can be defeated. Possible mechanisms include the loss of feedback inhibition of insulin receptor substate/PI3K signaling resulting from the inhibition of mTOR complex 1 by rapamycin analogs and the activating phosphorylation of Akt by mTOR complex 2. Laboratory studies indicate that these resistance mechanisms could be countered by using other targeted agents in combination with mTOR inhibitors.
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PMID:Targeting mTOR in renal cell carcinoma. 1940 72

The mammalian target of rapamycin (mTOR) has been shown to be an important target mechanism in the treatment of renal cell carcinoma (RCC). In first-line treatment for patients with disease having poor prognostic features, temsirolimus, an mTOR inhibitor approved for treatment of advanced rcc, has demonstrated benefit over interferon alfa in both overall and progression-free survival. Everolimus, a second mTOR inhibitor that has showed activity in rcc, led to improved progression-free survival in a comparison with placebo in patients whose rcc progressed after treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (sunitinib, sorafenib, or both). There is now compelling clinical evidence for the effectiveness of targeting mTOR in the treatment of RCC.
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PMID:Inhibition of mTOR in kidney cancer. 1947 99

The pharmacological management of systemic lupus erythematosus (SLE) is challenging owing to its unpredictable clinical course, the variable organ system involvement and the lack of clear understanding of disease pathogenesis. The widely used corticosteroids and immunosuppressive drugs, which can control disease activity, have serious, potentially fatal, side effects. In the last decade, a better understanding of lupus pathogenesis has led to the development of biological agents that are directed at biomarkers. However, these biologicals also exert side effects due to infections resulting from completely eliminating immune cells (e.g., B cells) or cytokine signals (e.g., interferon-alpha) or affecting molecular targets outside the immune system (CD40L on platelets). New biomarker-driven clinical trials are ongoing to evaluate the safety and efficacy of B-cell depletion, blocking of interferon signaling, inhibition of the mTOR pathway, and restoration of glutathione deficiency in lupus T cells.
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PMID:Pharmacotherapy of systemic lupus erythematosus. 1950 15

Tumor suppressor complex TSC1/TSC2 represents a key negative regulator of mammalian target of rapamycin (mTOR)-S6 kinase 1 signaling. Mutational inactivation of TSC1 or TSC2, linked to a rare lung disease, lymphangioleiomyomatosis (LAM), manifests as neoplastic growth of smooth-muscle (SM)-like cells and cystic destruction of the lungs that induces loss of pulmonary function. However, the precise mechanisms of abnormal cell growth in LAM remain uncertain. Here, we demonstrate increased signal transducer and activator of transcription (STAT) 3 expression, phosphorylation, and nuclear localization in SM-like cells in LAM lungs and in TSC2-null xenographic tumors. Treatment of TSC2-null tumors with mTOR inhibitor rapamycin attenuated STAT3 expression and phosphorylation. Increased STAT3 level and activation were also observed in LAM-dissociated (LAMD) cell cultures compared with normal human bronchus fibroblasts (HBFs) from LAM patients. Although interferon (IFN)-gamma inhibited proliferation of HBFs, IFN-gamma treatment had little effect on proliferation of LAMD and TSC2-null cells. Re-expression of TSC2 or treatment with rapamycin inhibited IFN-gamma-induced STAT3 phosphorylation and synergized with IFN-gamma in inhibiting TSC2-null and LAMD cell proliferation. Reduction of STAT3 protein levels or activity using specific small interfering RNA or inhibitory peptide, respectively, decreased proliferation and induced apoptosis in TSC2-null and LAMD cells and sensitized cells to growth-inhibitory and proapoptotic effects of IFN-gamma. Collectively, our data demonstrate that STAT3 activation is required for proliferation and survival of cells with TSC2 dysfunction, that STAT3 impedes growth-inhibitory and proapoptotic effects of IFN-gamma, and that TSC2- and rapamycin-dependent inhibition of STAT3 restores antiproliferative effects of IFN-gamma. Thus, STAT3 may provide a novel therapeutic target for diseases associated with TSC1/TSC2 dysfunction.
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PMID:Signal transducer and activator of transcription 3 is required for abnormal proliferation and survival of TSC2-deficient cells: relevance to pulmonary lymphangioleiomyomatosis. 1959 36

Cellular mechanisms involving the enhancement of interferon (IFN) signaling by ribavirin remain poorly understood. Here, we identified a novel role of ribavirin in the communication between p53 and the mammalian target of rapamycin (mTOR) signaling. Ribavirin activates p53 by stimulating mTOR and promoting the interaction between mTOR and p53. Activated p53 stimulates the transcription of IFN regulatory factor 9 and subsequently enhances IFN signaling. Furthermore, ribavirin-induced activation of mTOR and p53 enhances IFN-dependent signaling for the IFN-alpha/ribavirin combined treatment. We conclude that ribavirin enhances activities of mTOR and p53, which may account for its antiviral and antitumor effects.
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PMID:Ribavirin enhances interferon signaling via stimulation of mTOR and p53 activities. 1961 45

The mTOR signaling pathway plays a very important role in the transmission of signals for initiation of mRNA translation and protein expression in mammalian cells. mTOR activates various downstream effectors to promote initiation of cap-dependent mRNA translation and mediate pro-mitogenic and pro-survival signals. Recent evidence has implicated effectors of this signaling cascade in mRNA translation for interferon stimulated genes (ISGs). In addition, it was recently shown that AKT/mTOR-mediated signals play important roles in the generation of IFN-dependent antiviral and growth inhibitory responses, suggesting that mTOR and its effectors can mediate diverse biological responses, depending on the cellular context and the triggering stimuli. In this review, the regulatory effects of various growth suppressive cytokines on the mTOR pathway are summarized and the emerging new functions of mTOR are discussed.
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PMID:Growth suppressive cytokines and the AKT/mTOR pathway. 1968 19

In the last 5 years the paradigms for the treatment of metastatic renal cell cancer have fundamentally changed. Until 2005 systemic therapy was limited to the immunomodulating cytokines interferon-alfa and interleukin-2, in recent years, however, tyrosine kinase inhibitors, mTor inhibitors and monoclonal antibodies have been established for this therapeutic situation. Without validated predictive biomarkers it is currently not possible to select patients who are likely to benefit from a certain therapy. Therefore, most current guidelines stratify the patients into risk groups according to the MSKCC risk score. The resulting treatment algorithm for first-line therapy is limited to these new drugs within all risk groups. Since approval for more tyrosine kinase inhibitors and mTOR inhibitors is currently awaited, the number of treatment options will expand further in the near future. The present paper reviews the present study data and aims to provide practical advice for the treatment of patients suffering from metastatic renal cell cancer.
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PMID:[Systemic therapy of metastatic renal cell carcinoma: from many options to the therapeutic strategy]. 1980 42

Patients with metastatic renal cell cancer (mRCC) have traditionally had poor responses to systemic therapies. Recent developments in molecular biology have increased our understanding of the oncogenic processes and pathways in clear-cell mRCC. The development of drugs that target these pathways has expanded treatment options, improved prognosis and changed standard management of patients with clear-cell mRCC. Sunitinib, sorafenib and pazopanib (oral tyrosine kinase inhibitors) as well as everolimus and temsirolimus (mTOR inhibitors) and interferon with bevacizumab (an antibody to VEGF) have improved patient outcomes in large Phase III trials. These drugs have been incorporated into standard practice. Sunitinib has been adopted as first-line standard of care. Many agents are in development for treatment of mRCC, including axitinib in Phase III trials. We will review these treatments, their toxicities and how these targeted agents have impacted on mRCC.
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PMID:Impact of anti-angiogenic treatments on metastatic renal cell carcinoma. 1995 91

Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.73; 95% confidence interval, 0.58-0.92, P = .008) and progression-free survival (P <.001) compared with interferon alfa (IFN) for patients with poor prognostic features. Median progression-free survival durations were 3.8 and 1.9 months, respectively, for patients treated with temsirolimus or IFN, and median overall survivals were 10.9 and 7.3 months, respectively. Exploratory analyses indicate that temsirolimus benefits those patients with metastatic RCC and multiple adverse prognostic factors regardless of tumor histology or nephrectomy status. Most adverse events that occur in patients receiving temsirolimus can be managed medically (eg, hyperglycemia, hyperlipidemia) or addressed by supportive measures (eg, stomatitis, rash). Although development of symptomatic pneumonitis is rare, monitoring is recommended. Temsirolimus is now considered an important first-line treatment option for patients with advanced RCC and multiple factors predictive of short survival. Current trials are investigating the use of temsirolimus in sequence or in combination with other targeted agents to further improve outcomes.
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PMID:Clinical trial experience with temsirolimus in patients with advanced renal cell carcinoma. 1996 97

Renal cell carcinoma (RCC) is among the most resistant tumours to chemotherapy, radiotherapy and hormonal therapy. Cytokine therapy is effective in a small subset of patients, but it is associated with substantial toxicity and rarely benefits patients with extensive tumour burdens or adverse prognostic factors. Since 2005, clinical trials have shown significant clinical benefits for five molecularly targeted therapies in patients with advanced RCC. These agents constitute two mechanistic classes: (i) angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) ligand (bevacizumab, in combination with interferon-a) or VEGF receptors (sunitinib, sorafenib); and (ii) inhibitors of the mammalian target of rapamycin (mTOR) signalling (temsirolimus, everolimus). This review assesses the mechanistic distinctions and functional overlaps of these classes of agents, and discusses key characteristics of their respective clinical efficacy and side-effect profiles in patients with RCC, some of which might affect patient selection and treatment strategies. Current research is designed to optimize the use of these agents, as well as the development of new investigational therapies within these mechanistic classes. The differences and synergies are particularly important for understanding the best ways to integrate VEGF/VEGF receptor inhibitors and mTOR inhibitors for combination or sequential treatment of patients with advanced RCC.
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PMID:Vascular endothelial growth factor and mTOR pathways in renal cell carcinoma: differences and synergies of two targeted mechanisms. 2005 90


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