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)

Recent therapeutic strategies to combat organ allograft rejection have focused on T-cell signaling pathways and the molecules that comprise them. The macrolide antibiotic produced by the bacterium Streptomyces hygroscopicus, known as sirolimus or rapamycin, has shown great therapeutic potential in the transplant setting. Sirolimus alone or in combination with other immunosuppressive agents can block acute rejection, chronic graft destruction, and promote permanent allograft acceptance. Sirolimus targets a unique serine-threonine kinase, mammalian target of rapamycin (mTor), which plays a key role in mitogenic and nutritional cells signals. Within T cells, mTor regulates a number of proteins likely dependent on T cell growth factors such as interleukin 2. This review is focused on the molecular mechanisms by which mTor may regulate T-cell signaling cascades and affect T-cell responsiveness, and how sirolimus likely uncouples this activity.
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PMID:Molecular actions of sirolimus: sirolimus and mTor. 1274

Growth factors and hormones activate global and selective protein translation by phosphorylation and therefore activation of p70 S6 kinase through a wortmannin-sensitive phosphoinositide-3 kinase (PI-3K) antiapoptotic pathway and a rapamycin-sensitive signalling pathway of mTOR. Here we demonstrate that the phosphorylation of 40S ribosomal protein S6, a physiological substrate p70 S6 kinase, was highly increased by growth-stimulation of the cytolytic T cells (CTLL2) with interleukin 2 (IL2), which was accompanied with the increased phosphorylation of p70 S6K. The activity of p70 S6K and phosphorylation of the S6 protein was completely blocked by rapamycin and significantly decreased upon treatment of the cells with wortmannin, indicating an involvement of the PI-3K pathway in concert with the signalling pathway of mTOR in IL2-dependent phos-phorylation of ribosomal protein S6. The phosphorylation and activity of PKB/Akt in IL2-stimulated CTLL2 cells were rapamycin-insensitive and reduced upon wortmannin treatment of the cells, confirming a requirement for PI-3K for Akt activity. The data support the hypothesis that Akt may act downstream to PI-3K and upstream to mTOR in an IL2-mediated signal transduction pathway that controls phosphorylation of the regulatory protein S6 in CTLL2 cells.
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PMID:IL2-dependent phosphorylation of 40S ribosomal protein S6 is controlled by PI-3K/mTOR signalling in CTLL2 cells. 1501 Aug 63

CD28-deficient T cells arrest at the G1-S transition of the cell cycle. Here we show that this is controlled by the kinase aurora B, which exists in a complex with survivin and mammalian target of rapamycin (mTOR). Expression of aurora B in Cd28-/- T cells augmented phosphorylation of mTOR substrates, expression of cyclin A, hyperphosphorylation of retinoblastoma protein and activation of cyclin-dependent kinases 1 and 2 and promoted cell cycle progression. Interleukin 2 enhanced aurora B activity, and inactive aurora B prevented interleukin 2-induced proliferation. Moreover, expression of aurora B restored Cd28-/- T cell proliferation and promoted inflammation in vivo. These data identify aurora B, along with survivin and mTOR, as a regulator of the G1-S checkpoint in T cells.
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PMID:The kinases aurora B and mTOR regulate the G1-S cell cycle progression of T lymphocytes. 1712 76

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

Immunosuppressive drugs modulate cellular and humoral immune response in the acute allograft rejection. The panel of drugs, which has been recently extended, allowed a significant progress for immunosuppressive treatment. These drugs help us to improve our knowledge of lymphocyte activation pathways. Corticoids, the oldest immunosuppresive drugs, inhibit many cytokines such as interleukin 2 (IL2) and interleukin 6. They represent the treatment of acute rejection. The other immunosuppressive drugs are used for preventing acute rejection. After binding to a specific immunophillin, cyclosporin and tacrolimus inhibit calcineurine, a serine/threonine phosphatase which plays a major role in cytokines transcription notably IL2 after T-cell activation. Anti-IL2 receptor monoclonal antibodies block IL2 activity following T-cell activation. Protein mammalian target of rapamycin inhibitors avoid the transcription of different mRNA involved in the regulation of the cellular cycle. These new agents are rapamycin or sirolimus and everolimus. The inhibitors of pyrimidic and puric bases synthesis, mycophenolic acid and azathioprin, inhibit T- and B-cell proliferation. The wide variety of immunosuppressive drugs permits the use of combinations, which aims at decreasing the immunologic risk and their own toxicities, notably nephrotoxicity. Before transplant, the pharmacist plays an important role in the prevention of initial pathologies and in the politic of organ donation. After transplant, the pharmacist has a role in the pharmacological and biological monitoring of immunosuppressive drugs. But the pharmacist must be involved in the optimization of therapeutics and in the education of transplant patients.
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PMID:[Today in molecular mechanisms of immunosuppressive drugs actions: roles of pharmacist]. 1857 Sep 9

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

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 standard immunosuppression protocol after liver transplantation (LT) is based on an anticalcineurin (ACN) (tacrolimus or cyclosporine microemulsion) combined with mycophenolate and corticosteroids. Corticosteroids are usually stopped between 6 and 12 months after LT, except for patients whose transplantations were necessitated by autoimmune disease. ACN and mycophenolate must be monitored to verify the dose, with a residual blood assay (for tacrolimus), at 2hours (for cyclosporine microemulsion), or by a simplified area under the curve (for mycophenolate). The first-line treatment for rejection calls for increasing the dosage of tacrolimus (or switching to tacrolimus for patients treated with cyclosporine). Second-line treatment for refractory rejection is corticosteroid bolus (500-1000 mg of methylprednisolone, one to three times). Antibodies blocking the interleukin 2 receptors (basiliximab) or lymphocytes (thymoglobulin) make it possible to reduce the incidence of rejection, decrease corticosteroid doses rapidly and introduce ACN later on (useful in cases of kidney failure). The mTOR inhibitors (sirolimus and everolimus) have different side effects (hyperlipidemia, thrombocytopenia, and pulmonary, cutaneous, and articular events) than ACNs. The absence of any renal or vascular effect is interesting for patients with kidney failure, and the antiproliferative effect can be useful for patients transplanted because of cancer. The current objective of immunosuppression is to reduce the adverse effects (kidney failure, metabolic complications, cancer and infections, in particular, which reduce the survival of patients and grafts), and in the future, to promote the establishment of tolerance that ideally will allow the patient to stop prophylactic immunosuppressant treatment. New chemical agents, capable of acting on new and more specific pathways, are in phase II/III testing.
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PMID:[Immunosuppression after liver transplantation]. 1965 86

Despite recent advances, metastatic renal cell carcinoma remains largely an incurable disease. Vascular endothelial growth factor and mammalian target of rapamycin inhibitors have provided improvements in clinical outcomes. High-dose interleukin 2 remains an option for highly selected patients and is associated with durable remissions in a small minority of patients. The toxicity profiles of specific agents and patient characteristics and comorbidities and costs have an important role in the current choice of therapy. Major challenges encountered in developing molecular biomarkers to guide therapy are tumour heterogeneity and standardisation of tissue collection and analysis. Although biomarkers are in their infancy of development, they should be a priority in early preclinical and clinical development in order to guide rational tailored development of emerging agents.
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PMID:Biomarkers: the next therapeutic hurdle in metastatic renal cell carcinoma. 2294 24

Patients with metastatic melanoma had few treatment options until 2011, when two drugs-ipilimumab and vemurafenib-were approved following advances in the understanding of melanoma biology and tumour immunology. Almost 50% of melanomas harbour mutations in BRAF, mainly at codon 600, which result in constitutive activation of the MAPK pathway. The selective inhibitors of mutant BRAF Val600, vemurafenib and dabrafenib, showed major tumour responses, resulting in improved progression-free and overall survival in patients with metastatic disease, compared with chemotherapy. Antitumour activity was also recorded in brain metastases. The growth of cutaneous squamous-cell carcinomas is a unique side-effect of BRAF inhibitor therapy that is induced by the paradoxical activation of the MAPK pathway in cells with RAS mutations. Trametinib, which targets MEK downstream of BRAF, also produced an overall survival benefit compared with chemotherapy, although tumour responses were less frequent than they were with BRAF inhibitors. Despite this robust antitumour activity, most responses to these drugs are partial and disease progression is typically seen at a median of 5-7 months. Multiple resistance mechanisms have been identified, including those that lead to reactivation of the MAPK pathway and other pathways, such as the PI3K-AKT-mTOR and VEGF pathways. Some patients with BRAF Val600 mutant melanoma seem to also benefit from immunotherapies such as high-dose interleukin 2 and ipilimumab, which, by contrast with BRAF inhibitors, can produce durable complete responses. We review the available data to best guide initial treatment choice and the sequence of treatments for patients with BRAF Val600 mutant melanoma.
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PMID:Which drug, and when, for patients with BRAF-mutant melanoma? 2356 43


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