The macrocyclic lactone antibiotic rapamycin is a novel anticancer agent that specifically inhibits the activity of a protein kinase (mTOR) that controls translation of proteins involved in cell cycle progression and survival. Our studies in Project 1 have shown that the response to mTOR inhibition in normal and malignant cells is qualitatively different: Rapamycin causes G1 phase arrest and cytostasis in normal cells, whereas tumor cells with deficient G1 checkpoint function (p53/p21) transit G1 phase and undergo apoptosis. Insulin-like growth factor I (IGF-I) uniquely protects against apoptosis. Studies proposed will focus on combining CCI-779, a rapamycin ester undergoing clinical trials, with inhibitors of IGF-I signaling, and further determine the mechanism(s) responsible for acquired and intrinsic resistance to CCI-779. We will attempt to develop biochemical assays to measure mTOR inhibition in tumor tissue, and develop potentially novel combinations of CCI-779 in support of our proposed clinical studies in children when the agent is made available. Specific hypothesis to be tested are:1. Inhibition of IFG-I receptor signaling will prevent IGF-I protection against rapamycin-induced apoptosis, and promote apoptosis selectively in cells lacking wild type p53. 2. Regulation of 4E-BP protein levels is a critical determinant of rapamycin sensitivity. 3. Tumor response to high dose CCI-779 is dependent on mTOR inhibition, and is associated with prolonged inhibition of eIF4E-dependent translation. 4. The long-term goal of these studies is to develop alternative approaches to curative therapy for children (and adults) with cancer. This is based in part on an understanding of IGF-I receptor signaling in growth and survival of pediatric cancer cells, and partly on the observation that inhibition of mTOR signaling is selectively cytotoxic to cells that have aberrant p53/p21-dependent G1 checkpoints.
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