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)

Metastatic renal-cell carcinoma (mRCC) is highly resistant to cytotoxic agents or hormones and is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients with these aspecific biological response modifiers. Side-effects are considerable, especially with high-dose interleukin (IL)-2. Efforts made in the field of specific immunotherapy have focused on optimization of dendritic cell vaccination and on administration of monoclonal antibodies, either cold (unconjugated) or hot (radioactively labeled). Furthermore, allogeneic bone marrow transplantation is able to induce remissions but, regrettably, is related to substantial morbidity and mortality. Neutralization of the biological activity of some immunosuppressive cytokines produced by RCC (IL-6 and tumor necrosis factor-alpha) with monoclonal antibodies is currently under investigation. Insights gained into the processes and pathways underlying carcinogenesis have led to the development of new treatment strategies. These treatments can be used for clear cell RCC, since they focus on blocking gene products that are upregulated by mutations in the von Hippel-Lindau gene. Specific strategies include anti-vascular endothelial growth factor monoclonal antibody (bevacizumab) or inhibition of its receptor kinases (oral SU11248 or PTK787), or targeting the Raf kinase pathway (by BAY 43-9006) or the mammalian target of rapamycin (mTOR) pathway (by CCI-779). Early clinical results are promising, but their place in the treatment of RCC has to be determined.
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PMID:Novel treatment strategies in clear-cell metastatic renal cell carcinoma. 1602 18

Angiogenesis is an important hallmark of RCC, reflected in the natural history, Histology, genetics and now therapeutics of this disease. Clearly, the pro-angiogenic growth factor VEGF is a functional drug target in RCC and many strategies to inhibit this biology have shown clinical benefit. Multi-targeted TKI that inhibit VEGFRs have been approved by the FDA as standard treatment for advanced RCC. Pharmacodynamyc studies suggest that these agents and others also have anti-angiogenic effects. Currently, studies combining VEGFR-targeted strategies with other anti-angiogenic agents, including anti-VEGF antibodies, IFN or mTOR inhibitors, are underway. However, to what extent the clinical benefit of anti-angiogenic strategies in RCC can be built upon is unknown.
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PMID:Anti-angiogenic therapy in renal cell cancer. 1744 27

Renal carcinogenesis is promoted by overexpression of the activated serine/ threonine kinase Akt (p-Akt) and supposedly a concomitant reduction in phosphatase and tensin homologue deleted on chromosome 10 tumour suppressor gene (PTEN), which normally inhibits the activation of Akt. Because promising anti-cancer therapies increasingly focus on pathways involving p-Akt and PTEN, the present study evaluated the expression of p-Akt in renal cell carcinomas and compared it with prognosis. P-Akt and PTEN expression were analysed in a tissue microarray (TMA) from renal cell carcinoma (n = 386) and adjacent uninvolved renal tissue (n = 32) specimens. Increased p-Akt was found more often in the nucleus than in the cytoplasm, and PTEN was concomitantly reduced in about 50% of cases. Neither tumour grade nor stage influenced p-Akt expression, whereas the clear cell and papillary subtypes showed increased p-Akt more often than did the chromophobe or sarcomatoid types. Increased cytoplasmic and nuclear p-Akt levels were independent prognostic factors for diminishing patient survival. The present study found significantly increased nuclear but also cytoplasmic p-Akt expression in renal cell carcinoma subtypes. Increased nuclear and cytoplasmic p-Akt was an independent prognostic factor for diminishing patient survival. The considerable number of high-grade and high-stage RCC showing increased p-Akt and reduced PTEN would justify further evaluation of therapeutic concepts based on inhibitors of the PI3K/p-Akt/mTOR pathway.
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PMID:Increased activated Akt expression in renal cell carcinomas and prognosis. 1877 62

Cytokine-based therapeutic approaches using interferon (IFN) and interleukin 2 (IL-2) were conventionally applied for the treatment of progressive RCC. Caused by the limited effectiveness of cytokine-based approaches in advanced renal cell carcinoma, new substances were needed. Among these, the "targeted therapies", particularly the group of the tyrosine kinase inhibitors, are of main interest. At present, multikinase inhibitors and antiangiogenic agents (VEGFR, PDGFR-beta, and mTOR) are used in first- and second-line therapies of metastatic RCC in various clinical studies. This review presents and discusses the effectiveness of the most frequently used substances in mono- or combination regimes based on current data of the ASCO 2007.
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PMID:Novel therapeutic options in metastatic renal cancer - review and post ASCO 2007 update. 1878 79

Cytoreductive nephrectomy in combination with adjuvant immunotherapy is an established treatment option for selected patients with metastatic clear-cell renal cell carcinoma (mCC-RCC). Multitargeted antiangiogenic and mammalian target of rapamycin tyrosine kinase inhibitors (TKIs) are now established treatment paradigms in patients with mCC-RCC. Given that all the recent seminal TKI trials in mCC-RCC provide no evidence base for the use of cytoreductive nephrectomy in the TKI era, it is not presently clear where such a surgical approach fits into the treatment paradigm. This review summarizes the evidence for the management of mCC-RCC and outlines novel approaches to be tested within future trials if the initial proposed phase III trials in this setting, using sunitinib, are successful. Overall, two principal questions need addressing. First, is cytoreductive nephrectomy necessary in the TKI era? Second, if so, what is the most appropriate scheduling of TKI therapy with cytoreductive nephrectomy?
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PMID:Cytoreductive nephrectomy in metastatic clear-cell renal cell carcinoma: perspectives in the tyrosine kinase inhibitor era. 1914 92

FDA approval of the multitargeted, antiangiogenic tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib, and the serine and threonine mammalian target of rapamycin inhibitor, temsirolimus, has revolutionized the management of metastatic clear-cell renal-cell carcinoma (CC-RCC). The inability of these targeted therapies to provide durable complete responses, however, is a serious limiting factor to their clinical usefulness. Although immunotherapeutic approaches in advanced disease are increasingly regarded as a historical treatment paradigm, we propose that a fundamental understanding of immunobiology in CC-RCC can improve the selection of patients for high-dose intravenous interleukin 2 and facilitate the development of novel immunotherapeutic strategies. In our opinion, immunotherapeutic strategies have an important place in the management of advanced CC-RCC in the era of biological targeted therapy.
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PMID:Immunotherapeutic strategies in kidney cancer--when TKIs are not enough. 1954 65

The mammalian target of rapamycin(mTOR)and its molecular pathways are supposed to be activated frequently in human renal cell carcinoma as well as other cancers. It has a kinase activity for 40S ribosomal protein kinase and eukaryotic translation initiation factor 4E-binding protein 1. These proteins, when phosphorylated, promote protein translation and RNA transcription in the nutrient-rich condition. mTOR inhibitors such as Temsirolimus (CCI779) and Everolimus (RAD001) are effective for suppressing cell growth with inhibiting mTOR kinase activity. Rapamycin and its related analogs such as Temsirolimus and Everolimus are less toxic for humans compared with other anti-VEGFR inhibitors and has been used as an immunosuppressive agent. These agents have an inhibitory activity against the mTORC1 complex. Since they do not have inhibitory activity against mTORC2 complex, the ability of mTOR inhibition by Temsirolimus is supposed to be 40 to 50% of full inhibition in mTOR kinase. Temsirolimus has modest anticancer activity against advanced clinical RCC patients with poor risk. The objective response rate was only 7%, 26% of patients experienced minor responses and another 17% of patients had stable disease that lasted 6 months. The median time to tumor progression and median survival for the study patients were 5.8 and 15.0 months, respectively. The overall survival of patients treated with Temsirolimus alone was statistically longer than in those treated with IFN alone in the 626 cases in phase II study. Combinations of mTOR with other anti- VEGFR agents were not effective. Vertical therapies of mTOR inhibitor in combination with AKT inhibitors, or newly development of stronger mTOR kinase which can suppress both mTORC1 and mTORC2 are planned at present.
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PMID:[Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma]. 1962 Jul 95

Renal cell carcinoma therapy has changed in a very significant way in the last few years. Up to 5 new agents have been developed, improving the results previously achieved with cytokine therapy. Bevacizumab, sorafenib, sunitinib, temsirolimus, and everolimus are now part of the therapeutic arsenal for this illness. Particularly, this has been the first tumoral type in which inhibition of mammalian target of rapamycin (mTOR) has proved its efficacy in phase III trials, either as first-line therapy for poor prognosis patients (temsirolimus, CCI-779) or as second-line therapy after failure of tyrosine-kinase inhibitors (everolimus, RAD001). In this paper, we review the basis for mTOR inhibition in RCC, and discuss the results of the trials involving temsirolimus and everolimus for the treatment of this disease.
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PMID:mTOR pathway inhibition in renal cell carcinoma. 2020 76

Hypoxia-inducible factor (HIF) plays an important role in renal tumourigenesis. In the majority of clear cell RCC (ccRCC), the most frequent and highly vascularized RCC subtype, HIF is constitutively activated by inactivation of the von Hippel-Lindau gene. Of the HIF subunits, HIF-2alpha appears to be more oncogenic than HIF-1alpha, in that HIF-2alpha activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1alpha, more than HIF-2alpha, can undergo proteasomal degradation in VHL - /- RCC cells. A more detailed understanding of the molecular basis of hypoxia and angiogenesis in renal carcinogenesis has set the stage for the development of targeted therapies, inhibiting multiple HIF-related pathways, such as the phosphatidylinositol 3-kinase-AKT-mTOR, RAS/RAF/MAP, and VEGF signalling routes. However, despite the positive results of these targeting agents in progression-free survival, clinical resistance remains an issue. Recent pre-clinical studies have suggested new targeting approaches such as inhibition of HIF-driven key metabolic enzymes and have introduced new HIF targeting agents, such as histone deacetylase inhibitors, with successful anti-neoplastic effects. In this review, we discuss existing and novel findings about RCC carcinogenesis, with subsequent clinical implications.
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PMID:VHL and HIF signalling in renal cell carcinogenesis. 2022 41

Advanced renal cell carcinoma is associated with a poor prognosis and is refractory to standard chemotherapy. Recent progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies. The management of metastatic RCC has been revolutionized with the development of targeted molecular therapies against VEGF-VEGFR and mTOR. Randomized phase III clinical trials demonstrated clinical benefit for patients with advanced RCC in overall survival and progression free survival. At the moment, six molecules have been approves in advanced RCC: cytokines (IL-2 and IFN), antiangiogenic therapies (sunitinib, sorafenib, bevacizumab) and mTOR inhibitors (Temsirolimus, everolimus). Nephrectomy is an important component of the multimodality treatment of mRCC. Prospective trials will be assessed the value of nephrectomy in patients treated by antiangiogenic therapies. Large randomized trial are ongoing to evaluate these new therapies in adjuvant setting.
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PMID:[Renal cell carcinoma management and therapies in 2010]. 2041 1


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