Although the molecular details of mTOR function during the hypoxic adaptation remain very limited, preliminary studies performed in our laboratory indicated that this protein plays central roles in both the accumulation and transcriptional activation of HIF-1 under hypoxic conditions. A systematic analysis of the role of mTOR in upregulating HIF-1 transcriptional activity in PCa cells will clearly enhance our current understanding of the biology of late-stage prostate cancer. The relevance of the current proposal is further increased by the fact that inhibitor of mTOR function, RAPA is already in the clinic as an immunosuppressive agent. Direct evidence has emerged that RAPA could have activities against cancer development through a potent anti-angiogenic action, which is linked to reduction of vascular endothelial growth factor (VEGF), a downstream target of HIF-1. Furthermore, a RAPA analog, CCI-779 (Wyeth-Ayerst) has entered Phase II trials in cancer patients, and, based on encouraging preliminary results, PCa is considered a prime disease target. However, our current level of understanding regarding the mechanisms of RAPA/CCI-779 affecting the biology of PCa or other cancer cell types remains at an early stage. We are particularly interested in studying the impact of RAPA treatment on parameters related to the growth and survival of PCa cells. The specific objectives of this project are to explore: (1) to define the mechanism by which RAPA inhibits stabilization HIF-1alpha in hypoxic cells and (2) to determine whether the antitumor activity of RAPA is linked to inhibition of HIF-1 alpha function in tumor xenograft in mice.
| Liu, Mei; Howes, Amy; Lesperance, Jacqueline et al. (2005) Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer. Cancer Res 65:5325-36 |
