mTOR Signaling Pathway

What is mTOR

• mTOR is a large, polypeptide, serine/threonine-specific kinase of the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family.²
• mTOR lies downstream of the PI3K pathway.²
• mTOR functions as an important intermediary in a variety of cell signaling events to regulate not only cell growth and cell proliferation, but also angiogenesis and cell survival.^2,3
• mTOR controls the cell replication process^3,4 by controlling the translation of key proteins that are required for the progression of the cell cycle through the G₁ to the S phase.^2,3

mTOR: an important pathway in advanced RCC

In cancer cells, multiple mechanisms of dysregulation within the PI3K pathway upstream of mTOR have been documented, causing increased mTOR activity, and consequently increasing tumor growth.³

mTOR inhibition may block the translation of cell-cycle regulatory proteins and inhibit the overexpression of angiogenic growth factors that contribute to cell survival.^5,6 Several mechanisms are thought to be involved:

• When mTOR is activated, it phosphorylates 2 proteins – the eukaryotic initiation factor 4E binding protein-1, also known as 4E-BP1, and the 40S ribosomal protein S6 kinase, also known as p70S6 kinase– that start the cell cycle protein translation process. Consequently, inhibition of mTOR activity produces cell cycle arrest, stopping cell division from the G₁ to the S phase.²
• mTOR also regulates other potential effectors of carcinogenesis. An example is hypoxia-inducible factor (HIF), which is involved in angiogenesis and the transcription of proteins such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), and other angiogenic and growth-stimulating molecules.^6,7

mTOR signaling

mTOR primarily controls cell proliferation and cell growth through two downstream pathways – p70S6K and 4E-BP1.^3,4

mTOR inhibition for advanced renal cell carcinoma

TORISEL^® (temsirolimus) is an mTOR inhibitor approved for treating patients with advanced RCC.

Learn more about temsirolimus studies and other clinical trials conducted by Wyeth.

 

TORISEL Important Safety Information

• Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL.
• Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL.
• The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.
• The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
• Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics.
• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.
• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL.
• Due to abnormal wound healing, use TORISEL with caution in the perioperative period.
• Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.
• Live vaccinations and close contact with those who received live vaccines should be avoided.
• Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.
• The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).
• Most common grades 3/4 adverse events and lab abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).
• Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.
• St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.
• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

Please see full Prescribing Information for TORISEL.

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References:

1. TORISEL^® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc.
2. Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett. 2005;10:479-497.
3. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4:335-348.
   
4. Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol. 2005;23:5386-5403.
5. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev.
   2004;18:1926-1945.
6. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22:7004-7014.
7. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909-918.

 

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