) Regulated cell signaling is critical in neoplastic cell transformation and proliferation. Novel anticancer agents interrupting different points in cell signaling pathways are entering the clinic. Rapamycin is a novel immunosuppressive agent targeting a single protein mTOR, which appears to function in a previously unrecognized signal transduction pathway necessary for G1/S phase cell cycle transition. Rapamycin has anti-proliferative activity in a variety of tumor cell types. This application utilizes rapamycin and its analogues as a focus in developing a career in clinical developmental therapeutics. The applicant proposes to: 1. utilize the rapamycin analogues as a model for the development of anticancer agents inhibiting intracellular signaling pathways. a. Rapamycin analogues with growth inhibitory activity will enter clinical trials shortly. Anti-proliferative effects have been seen in cell types which express EGF and PDGF receptors. Preliminary studies, however, indicate that the critical growth factor determining the sensitivity of tumor cells to the rapamycin analogues is IGF. In these clinical studies, the dependence of tumor sensitivity on EGF, PDGF, and IGF expression will be tested in tumor tissue samples (immunohistochemistry) and patient serum (serum immunoassay). b. Content of the target protein mTOR and one of its putative targets p70K in tumor tissue samples will be assayed via immunoblotting. Results will be correlated with tumor response to rapamycin. c. Since these agents are predominantly cytostatic, combination regimens will be tested initially in vitro utilizing clonogenic assays. The novel signal transduction regulator mTOR, which is the target of these agents, stimulates cell proliferation via a ras-independent pathway. Thus candidate drugs for combination studies will include (I) other cell signaling agents interfering with the ras pathway such as the farnesylation inhibitors, and (ii) classical cytotoxic agents which are non-cycle dependent such as the platinum analogues. 2. improve expertise in clinical drug development research through attending courses in biostatistics, phase I clinical trial design, involvement in pharmacokinetic/drug metabolism analyses, scientific meetings (Gordon Conference, AACR special meetings, EORTC-NCI new drug symposia).
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