This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Gleevec has shown activity in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors via potent activity against Bcr-Abl, platelet-derived growth factor receptor, and the C-Kit activated tyrosine kinase pathway. Paclitaxel has broad antitumor activity on microtubules via its action on microtubular assembly and stabilization of the microtubules against depolymerization, thereby inhibiting cellular proliferation by inducing a sustained mitotic block at the metaphase-anaphase portion of the cell cycle. Previous preclinical studies have shown significant synergistic effects when other chemotherapy agents have been combined with Gleevec, however Paclitaxel has not been evaluated in such a comparison. By combining the broad acting agent Paclitaxel with the new agent Gleevec we may observe additive or even synergistic effects without significant increases in toxicities secondary to independent antineoplastic mechanismsSPECIFIC AIMS:Primary Aims:+ Determine the dose-limiting toxicity and maximum tolerated dose of Gleevec and Paclitaxel when given in combination to patients with advanced tumors.+ Characterize the pharmacokinetics of Gleevec and Paclitaxel when given in combination.Secondary Aims:+ Document any objective antitumor response in patients treated with Gleevec and Paclitaxel.+ Document the relationship between C-Kit and platelet derived growth factor receptor (PDGF-R) expression on tumor biopsies and tumor response to the combination of Gleevec and Paclitaxel.Additional Cohort Objectives:+ Document any relationship between C-Kit and PDGF-R expression on tumor biopsies and tumor response to Gleevec and Paclitaxel in Taxane refractory breast cancer patients.+ Document any relationship between C-Kit and PDGF-R expression on tumor biopsies and tumor response to Gleevec and Paclitaxel in Taxane refractory Non-Small Cell Lung Cancer patients.Hypothesis: To determine the safety of combining these two potential anti-angiogenic agents.
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