Our laboratory was the first to report that IGF-I blocks TGF-(3 induced apoptosis and/or growth arrest by suppressing the activation of Smad3 through an IGF-l/P13K/Akt/mT0R-dependent mechanism. Preliminary data support that the IGF-l/P13K/Akt/mT0R pathway also intercepts BMP signaling. Our data also suggest that rapamycin, a potent mTOR inhibitor currently in phase II clinical trials for prostate cancer, activates Smads 1, 5 or 8. Our plans here are to elucidate the mechanisms by which the above IGF-I pathway affects BMP signaling. This investigation is likely to have therapeutic benefit, by helping to identify patients who may best benefit from mTOR inhibitors, and in optimizing therapeutic strategy. IGF-I pathway has been known to be upregulated during late stage prostate adenocarcinoma, whereas there is a loss of BMP- receptor function observed during late stage prostate cancer. The specific hypothesis to be tested is that the IGF-I suppresses BMP4-induced cell death through the PI3K/Akt/mT0R-dependent mechanism. We also hypothesize that inhibition of mTOR by rapamycin suppresses growth of prostate cancer cells or promotes their death through a mechanism involving Smad activation. Important to cancer therapeutics, our collaborator Dr. Jorge Garcia is conducting a phase II clinical trial at the Cleveland Clinic Foundation (CCF) with a rapamycin analogue, RAD001. Normal and malignant prostate tissue cores from biopsies and prostatectomies of patients treated with RAD001 will be made available for us to analyze immunohistochemically the expression of phospho-Smads and components for the IGF-l/PI3K/Akt/mT0R and BMP pathways. Expression levels of these markers will be correlated to disease severity and followed up by disease-free survival. All in all, these studies will elucidate the role of the TGF-(3 superfamily in the tumor suppression by rapamycin for prostate cancer.
The specific Aims of this proposal are:
Specific Aim 1 : To test the hypothesis that IGF-I suppresses BMP4-induced cell death through a PI3K/Akt/mT0R dependent mechanism.
Specific Aim 2 : To test the hypothesis that rapamycin reverses mTOR-mediated inhibition of the TGF-p superfamily pathway, thus leading to enhanced Smad activation in PCS cell line both in vitro and in vivo. This study will define the role of IGF-l/PI3K/Akt/mT0R and limiting BMP-induced apoptosis and rapamycin is able to reverse such inhibition. All in all, the study will provide a clear and comprehensive assessment of the molecular mechanisms of rapamycin's action in prostate cancer therapy.
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