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)

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

Constitutive tyrosine kinase (TK) activity of p210 BCR-ABL fusion protein of chronic myeloid leukemia (CML) usurps physiological functions of normal p145 c-ABL protein. Accordingly, its inhibition by imatinib mesylate (IM) lets p145 c-ABL translocate into the nuclear compartment, which drives cell growth arrest and apoptotic death. Here we show that IM and the mammalian target of rapamycin (mTOR) inhibitor RAD001 (Everolimus) have additive effects on BCR-ABL-expressing cells. Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c-ABL through events encompassing post-translational modifications of p145 c-ABL (Thr(735) phosphorylation) precluding its nuclear export and of 14-3-3 sigma (Ser(186) phosphorylation by c-Jun N-terminal kinase [JNK]) promoting p145 c-ABL nuclear re-import.
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PMID:mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein. 1964 77

Responsible factors in progressive tubular dysfunction in chronic renal failure have not been fully identified. In the present study, we hypothesized that the mammalian target of rapamycin, mTOR, was a key molecule in the degenerative and progressive tubular damage in chronic renal failure. Everolimus, an mTOR inhibitor, was administered for 14 days in 5/6 nephrectomized (Nx) rats at 2 and 8 weeks after renal ablation. Marked activation of the mTOR pathway was found at glomeruli and proximal tubules in remnant kidneys of Nx rats. The reduced expression levels of the phosphorylated S6 indicated the satisfactory pharmacological effects of treatment with everolimus for 14 days. Everolimus suppressed the accumulation of smooth muscle alpha actin, infiltration of macrophages and expression of kidney injury molecule-1 in the proximal tubules. In addition, everolimus-treatment restored the tubular reabsorption of albumin, and had a restorative effect on the expression levels of membrane transporters in the polarized proximal tubular epithelium, when its administration was started at 8 weeks after Nx. These results indicate that the constitutively activated mTOR pathway in proximal tubules has an important role in the progressive tubular dysfunction, and that mTOR inhibitors have renoprotective effects to improve the proximal tubular functions in end-stage renal disease.
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PMID:mTOR inhibitor everolimus ameliorates progressive tubular dysfunction in chronic renal failure rats. 1966 Apr 39

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in at least 50% of sporadic clear-cell renal cell carcinoma (RCC). This leads to a pseudohypoxic state in which the pVHL complex does not degrade hypoxia-inducible factor. Subsequent intracellular hypoxia-inducible factor accumulation results in increased production of growth factors such as VEGF, responsible for angiogenesis, tumor proliferation and mitogenesis. Recently, a number of strategies have been designed to specifically target these pathways. The VEGF, its related receptor and the mammalian target of rapamycin (mTOR) signal transduction pathway, in particular, have been utilized as therapeutic targets. Clinical trials have demonstrated the survival benefit of these agents, particularly in clear-cell RCC. Today, sunitinib is recommended as first-line therapy for intermediate- or low-risk patients with metastatic RCC. Sorafenib is advised as second-line therapy, whereas temsirolimus is generally recommended as first-line treatment in high-risk patients. Everolimus is the new standard following sunitinib. High-risk patients appeared to benefit less than low-risk patients from bevacizumab plus IFN-alpha therapy. High-dose IL-2 has been proven effective in prolonging progression-free survival or overall survival, depending on risk group selection criteria. Although novel agents show a consistent effect as measured by objective response, no currently available data demonstrate that these agents will cure any patient.
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PMID:Systemic therapy of kidney cancer: tyrosine kinase inhibitors, antiangiogenesis or IL-2? 1966 36

Metastatic renal cell carcinoma (RCC) is notoriously chemoresistant; up until recently, immunotherapy (in particular interferon-alpha) has represented the treatment of choice. The understanding of the biology of RCC has resulted in the development of targeted therapies. In particular, multikinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib), antivascular endothelial growth factor agents (bevacizumab), and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) now have a role in the approach to different subsets of RCC. Sunitinib is indicated for the first-line therapy of metastatic RCC as a consequence of a positive phase III trial versus interferon-alpha; sorafenib is now registered for the second-line treatment of RCC, which was earlier treated with cytokine as a consequence of a positive phase III trial versus placebo. Bevacizumab is also indicated in the first-line treatment of metastatic RCC given in combination with interferon-alpha as a consequence of two positive phase III trials. Temsirolimus, unlike the other agents, has also shown activity in poor-prognosis patients, and is now the treatment of choice in previously untreated poor-prognosis RCC as a single agent. Everolimus can be considered as the best therapeutic option in patients with RCC pretreated with targeted agents as a consequence of a positive phase III study versus best supportive care. Markers for appropriate treatment selection, combined use of targeted agents, treatment of special histologies, and adjuvant and neoadjuvant setting represent important special issues to be dealt with in future studies.
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PMID:New treatment approaches in renal cell carcinoma. 1975 18

The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC). Everolimus (RAD 001) is an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1) conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P </= 0 0.001). Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.
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PMID:Role of everolimus in the treatment of renal cell carcinoma. 1977 11

Everolimus is an orally administered, targeted therapy indicated for the treatment of advanced renal cell carcinoma. It inhibits the mammalian target of rapamycin, an integral component of multiple pathways involved in cell growth and proliferation. Median progression-free survival was significantly longer with everolimus 10 mg once daily than with placebo in both second interim (4.0 vs 1.9 months) and updated (4.9 vs 1.9 months) analyses of a randomized, double-blind, placebo-controlled, multicentre, phase III trial in patients with metastatic renal cell carcinoma that had progressed while receiving sunitinib and/or sorafenib treatment. At the second interim analysis, median overall survival was 8.8 months for placebo recipients; at this analysis, overall survival had not yet been reached for everolimus recipients. With regard to objective response at the second interim analysis, 64% of everolimus and 32% of placebo recipients had either a partial response (1% and 0%) or stable disease (63% and 32%). The tolerability profile of everolimus was largely manageable in the phase III trial, with most treatment-related adverse events being of grade 1 or 2 severity.
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PMID:Everolimus: in advanced renal cell carcinoma. 1979 29

The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.
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PMID:Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. 1986 Sep 3

Cardiac transplantation is a time-honored therapy for end stage heart disease for a select group of patients. The advances in recent years have increased mean survival to 12 and 13 years. The probability of survival after heart transplantation at one, five and ten years are 80%, 70% and 60% respectively. Calcineurin-inhibitors (CNIs) based regimes have been the corner stone of medical therapy in these patient populations. They have reduced the amount of rejections but with considerably increased toxicities to therapies that decreases long-term patient survival. Proliferation Signal Inhibitors or mammalian target-of-rapamycin inhibitors (PSI/mTOR) are a new class of agents that have been extensively used recently to limit these toxicities. Sirolimus and Everolimus are two such drugs. PSI/mTOR work syngeristically with CNIs or have been as primary immunosuppressant's for patients who do not tolerate or have developed side effects to calcineurin inhibitors. This current article will discuss about sirolimus and its use in heart transplant patients along with outlining some recent patents.
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PMID:Sirolimus: a novel immunosuppressive drug in heart transplantation. 1992 39

PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.
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PMID:Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. 1993 12


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