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

Advanced renal cell carcinoma remains resistant to drug-, hormone-, and cytokine-based therapies. Promising new immunotherapeutic approaches include monoclonal antibodies, kinase inhibitors, mammalian target of rapamycin inhibition, dendritic cell, and tumor antigen vaccines. Most of these approaches have yet to produce clinical responses significantly superior to those of previous standard therapies, although most are well tolerated and elicit relatively high rates of stable disease. Two recently approved agents, a kinase inhibitor and a mTOR inhibitor, are recommended for use as first-line therapies against renal cell carcinoma. An additional approved tyrosine kinase inhibitor, sorafenib, is recommended as second-line therapy. More clinical research on these agents and their use in combination, especially sequentially, is warranted.
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PMID:Current immunotherapeutic strategies in renal cell carcinoma. 1802 54

Until 2006, immunotherapy (interferon-alpha or interleukin 2) was the standard medical treatment for metastatic renal cell carcinoma (RCC), and its results were disappointing: despite a few cases of complete response with prolonged survival, median survival was one year. Better understanding of the molecular mechanisms of tumor angiogenesis, especially in clear cell carcinoma, has led to the development of multiple targeted therapies to inhibit key effectors: vascular endothelial growth factor (VEGF), VEGF receptor, and mTOR (target of rapamycin). Two inhibitors targeting several protein kinases, including the VEGF receptor, have increased progression-free survival in patients with metastatic RCC and are now commercially available: sunitinib (Sutent) as first-line treatment and sorafenib (Nexavar) as second-line treatment. These targeted therapies will certainly affect overall survival, but it is too early for any firm conclusions. Their side-effects, usually low or moderate, include asthenia, anorexia, diarrhea, hand-and-foot syndrome and hypertension. Optimal management is required to ensure prolonged exposure. Other drugs have been effective: bevacizumab (Avastin), a monoclonal antibody inhibiting VEGF, increases progression-free survival as second-line treatment, and temsirolimus (Torisel), an mTOR protein kinase inhibitor, increases overall survival in the population of patients with poor prognosis. These targeted drugs will serve as the basis for development of future therapeutic strategies.
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PMID:[Renal cell carcinoma and antiangiogenic therapies]. 1803 17

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

After decades of therapeutic nihilism in the treatment of advanced renal cell carcinoma, remarkable therapeutic strides have been made over the last few years. Early forays into molecularly targeted therapy for this difficult-to-treat disease were based around the inhibition of gene products of the hypoxia-inducible factor (HIF) transcription factor (i.e., VEGF). Recent data suggest that inhibition of mTOR results in clinical benefit in patients with poor prognostic features, and in preclinical models this therapeutic effect involves downregulation of HIF. Intriguingly, patients with nonclear cell histology appeared to obtain clinical benefit when treated with mTOR inhibitors. This review will highlight the mTOR pathway, its relevance to both clear cell and nonclear cell renal cell carcinoma, and its place in the host of quickly expanding treatment options.
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PMID:mTOR pathway in renal cell carcinoma. 1827 68

We previously reported that tumour-associated caveolin-1 is a potential biomarker in renal cell carcinoma (RCC), whose overexpression predicts metastasis following surgical resection for clinically confined disease. Much attention has recently focused on the AKT/mTOR pathway in a number of malignancies, including RCC. Since caveolin-1 and the AKT/mTOR signalling cascade are independently shown to be important regulators of tumour angiogenesis, we hypothesised that caveolin-1 interacts with the AKT/mTOR pathway to drive disease progression and metastasis in RCC. The aims of this study were to determine (i) the expression status of the activated AKT/mTOR pathway components (phosphorylated forms) in RCC and (ii) their prognostic value when combined with caveolin-1. Immunohistochemistry for caveolin-1, pAKT, pmTOR, pS6 and p4E-BP1 was performed on tissue microarrays from 174 clinically confined RCCs. Significantly decreased mean disease-free survival was observed when caveolin-1 was coexpressed with either pAKT (2.95 vs 6.14 years), pmTOR (3.17 vs 6.28 years), pS6 (1.45 vs 6.62 years) or p4E-BP1 (2.07 vs 6.09 years) than when neither or any one single biomarker was expressed alone. On multivariate analysis, the covariate of 'caveolin-1/AKT' (neither alone were influential covariates) was a significant influential indicator of poor disease-free survival with a hazard ratio of 2.13 (95% CI: 1.15-3.92), higher than that for vascular invasion. Tumours that coexpressed caveolin-1 and activated mTOR components were more likely to be larger, higher grade and to show vascular invasion. Our results provide the first clinical evidence that caveolin-1 cooperates with an activated AKT/mTOR pathway in cancer and may play an important role in disease progression. We conclude that evaluation of the 'caveolin-1/AKT/mTOR axis' in primary kidney tumours will identify subsets of RCC patients who require greater postoperative surveillance and more intensive treatment.
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PMID:Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma. 1828 22

This study was undertaken to interrogate cancer cell survival during long-term hypoxic stress. Two systems with relevance to carcinogenesis were employed: Fully transformed BJ cells and a renal carcinoma cell line (786-0). The dynamic of AMPK activity was consistent with a prosurvival role during chronic hypoxia. This was further supported by the effects of AMPK agonists and antagonists (AICAR and compound C). Expression of a dominant-negative AMPK alpha resulted in a decreased ATP level and significantly compromised survival in hypoxia. Dose-dependent prosurvival effects of rapamycin were consistent with mTOR inhibition being a critical downstream mediator of AMPK in persistent low oxygen.
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PMID:AMP-activated protein kinase is essential for survival in chronic hypoxia. 1835 90

The emergence of targeted therapies for advanced renal cell carcinoma has been a dramatic turning point in improving outcomes for the majority of patients with this disease. In study populations comprising primarily good- and intermediate-risk patients with clear cell renal cell carcinoma and prior nephrectomy, prolonged progression-free survival was demonstrated for three angiogenesis-targeted agents: sunitinib (compared with interferon [IFN]), bevacizumab plus IFN (vs IFN alone) and sorafenib (vs placebo in cytokine-refractory patients). As a first-line treatment for patients with multiple poor-risk factors, temsirolimus, which inhibits mTOR, has improved not only progression-free survival compared with IFN but, more importantly, overall survival. Further studies are needed to determine whether combinations and/or sequencing of these targeted agents can further improve outcomes.
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PMID:Improving outcomes in patients with advanced renal cell carcinoma. 1836 95

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

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'.
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PMID:[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. 1838 Mar 84

Recent advances in understanding the molecular events associated with renal cell carcinoma (RCC) are revolutionizing the therapeutic options offered for patients with advanced-stage RCC. These targeted approaches for RCC are based primarily on antiangiogenesis and/or specific kinase inhibitors targeting the vascular-endothelial growth factor and platelet-derived growth factor receptors, Raf and mammalian target of rapamycin inhibitor. In this context, characterization of the molecular events unique to RCC is also of critical significance for gene therapy endeavors. The attributes of gene therapy for RCC may include true targeting to cancer cells, transfer of immunomodulatory or antiangiogenic genes and novel nonapoptotic cancer cell killing mechanisms. Gene therapy may thus become a promising new adjuvant modality for RCC and expand the therapeutic armamentarium against RCC. Beyond the current stage of preclinical proof of principle and toxicological analysis in animal models, the utility of RCC gene therapy will depend on safety and efficacy trials in human subjects. These trials will determine whether targeted therapy for RCC employing genome-based strategies will broaden the current therapeutic spectrum for RCC comprising kinome-based, immunomodulatory and antiangiogenesis strategies.
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PMID:Gene therapy for renal cancer. 1839 90


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