Gary G. Chiang, Ph.D. - US grants

DESCRIPTION (provided by applicant): Rapamycin is a clinically useful immunosuppressant that has promising anti-tumor activities. Rapamycin specifically inhibits the function of a protein kinase called the mammalian Target of Rapamycin (mTOR); however, the molecular mechanism of inhibition is poorly understood. The mammalian Target of Rapamycin belongs to the family of phosphatidylinositol-3-kinase-related kinases (PIKKs) and plays a central role in cell growth and proliferation. Accumulating evidence suggests that mTOR is a downstream target of the PI3K/Akt signaling pathway, which is frequently deregulated in many types of cancer. While mTOR regulates the translation of mRNAs critical to G1/S progression, recent evidence also implicates mTOR in the regulation of HIF-1, a transcription factor important for the hypoxic adaptation of tumor cells. We hypothesize that the aberrant activation of the PI3K/Akt/mTOR pathway plays a critical role in the growth, proliferation, and hypoxic adaptation of tumor cells. The overall goal of this revised proposal is to improve our knowledge regarding the contribution of mTOR to cancer progression, with specific emphasis on the regulation of mTOR via signaling through PI3K/Akt. This objective will be pursued by addressing the following specific aims: (1) to define the mechanism by which Ser 2448 phosphorylation regulates mTOR function and (2) to dissect the regulation of mTOR function by the Tsc1/Tsc2 tumor suppressor complex.

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.