Targeting mTOR for Cancer Therapy

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DESCRIPTION (provided by applicant): Serine/threonine kinase mTOR (mammalian target of rapamycin) is a central regulator of cell growth and proliferation that modulates the transcription and translation of critical cell cycle regulatory molecules. Rapamycin and its analogues are in clinical trials, but have induced clinical responses in only a subgroup of patients. Therefore, there is a pressing need to identify biomarkers that can predict and monitor treatment response. We hypothesize that rapamycin modulates breast cancer biology by altering the expression of specific genes encoding for critical cell cycle and survival molecules. These gene products can be used to monitor response, and to determine which tumors will have significant growth inhibition. In specific Aim 1, we will determine the effect of rapamycin on the transcriptional, translational, and proteomic profile, and identify changes that occur in rapamycin-sensitive but not in rapamycin-resistant cells. We will determine the role of rapamycin-regulated genes in growth inhibition mediated by rapamycin. Then we will determine the effect of rapamycin analogue CCI-779 on the protein levels of selected targets in breast and prostate cancer patients treated with preoperative CCI-779. In Aim 2, we will evaluate cyclin D1 and BAG-1 as pharmacodynamic markers of response. We will determine the mechanism of rapamycin-mediated cyclin D1 and BAG-1 downregulation, and their role in growth-inhibition. In Aim 3, we will determine rapamycin's effect on DNA synthesis, protein synthesis, and glucose uptake in vivo by positron emission tomography and determine whether these studies may be early predictors of response. In Aim 4, we will determine whether mTOR activity predicts chemoresistance in breast cancer patients treated with preoperative chemotherapy. In addition, we will determine the mechanism of rapamycin-mediated enhancement of chemotherapy-induced cytotoxicity. With this study, we not only expect to identify pharmacodynamic markers of response for mTOR inhibitors but also to significantly enhance our understanding of mTOR inhibitors' mechanism of action.