Cellular Pharmacology of Rapamycin

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DESCRIPTION (provided by applicant): Rapamycin is a clinically approved immunosuppressive agent that has displayed significant antitumor activities in both rodent model systems and clinical cancer trials. The cellular activities of rapamycin reflect the inhibition of a single protein target, termed the mammalian Target of Rapamycin (mTOR). This large (approximately 290 kD) protein kinase is a member of a novel family of signaling proteins termed phosphoinositide (PI) 3-kinase related kinases, which collectively play key roles in cell growth control and genome surveillance in mammalian cells. Accumulating evidence suggests a strong link between deregulated signaling through the PI 3-kinase - AKT pathway and the sensitivity of cancer cells to the anti-proliferative effects of rapamycin. Aberrant PI 3-kinase signaling is characteristic of many late-stage, aggressive tumors, including glioblastoma, melanoma, and cancers of the prostate and breast. The overall goals of this project are define the signaling functions of mTOR in cancers, and to further understand the impact of rapamycin on mTOR-dependent responses relevant to cancer progression. In addition, we intend to explore in detail the interplay between the PI 3-kinase -mTOR signaling pathway and hypoxic adaptation, a key step in tumorigenesis. The specific aims of the current proposal are: (1) to compare the effects of rapamycin versus genetically-induced mTOR deficiency on cancer cell proliferation and tumorigenic activity, (2) to define the roles of mTOR in hypoxia-induced HIF-1alpha accumulation in cancer cells, and (3) to examine the role of hypoxia-induced factor (HIF)-1 inhibition in the anticancer activity of rapamycin.