The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to a family of phosphatidylinositol kinase-related kinases, which mediate cellular responses to stresses such as DNA damage and nutrient deprivation. mTOR acts as a target for the cell cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. mTOR plays a critical role in controlling cell growth, since it receives stimulatory signals from Ras and PI-3 kinase downstream from growth factors, as well as information on nutrient levels in the form of amino acid, glucose and oxygen availability. Its function is to integrate extracellular signals with amino acid availability and energy status of the cell and modulate translation rates of the proteins and other metabolic events accordingly. mTOR phosphorylates eIF4E binding proteins and the ribosomal protein S6 kinases to regulate protein translation rates, and its activity is closely associated with a 12-kDa immunophilin FK506-binding protein (FKBP12). mTOR inhibitors have been identified as promising agents for cancer prevention and/or therapy.

The cell cycle inhibitor temsirolimus (CCI-779) works by specifically inhibiting mTOR-driven cell proliferation. Based on its promising anticancer activity, temsirolimus has been evaluated in a range of oncology indications including renal cell carcinoma, lymphoma, leukemia, sarcoma, glioblastoma, melanoma, non-small cell lung, ovarian, prostate, breast and endometrial cancers and more. In late May, the U.S. FDA approved temsirolimus for the treatment of renal cell carcinoma (RCC). The rapid approval of temsirolimus in the U.S. was facilitated by both fast-track and priority review status. Temsirolimus has orphan drug status in both the U.S. and E.U. for the renal cell carcinoma indication.

In a three-arm, phase III trial of 626 patients with advanced RCC and poor prognosis who had received no prior systemic therapy, temsirolimus significantly increased median overall survival by 49% compared to interferon alpha (10.9 months vs. 7.3 months). The mTOR inhibitor also was associated with a statistically significant improvement over interferon alpha in the secondary endpoint of progression-free survival (5.5 months vs. 3.1 months). The combination of temsirolimus and interferon alpha did not result in a significant increase in overall survival when compared with interferon alpha alone (Hudes, G. et al., New Engl J Med 2007, 356(22): 2271-81).

Drug manufacturer Wyeth plans to launch temsirolimus (Torisel™) in July. As part of a postmarketing commitment, Wyeth has agreed to submit two completed study reports and data sets: one on a thorough QT prolongation study and one on an ongoing hepatic impairment study.

The information in this summary was derived from Prous Science Integrity® and is current as of June 26, 2007. For continuously updated information on temsirolimus, including new bibliographical references, clinical trials, regulatory information, patents and more, consult Integrity®.