Docetaxel (Taxotere) and Imatinib Mesylate (Gleevec) in Hormone Refractory Prostate Cancer

Androgen-independent prostate cancer is the second most common cause of cancer death in men. These patients have limited treatment options. Docetaxel(Taxotere) is the single most active agent for the treatment of hormone refractory prostate cancer. Phase II clinical trials including docetaxel combinations with other microtubule inhibitors have shown 60-70% prostate specific antigen (PSA) declines greater than 50% and 30-40% measurable disease responses. However, the duration of response is limited to roughly 22 weeks. Combinations with new agents are needed to increase the rate and duration of response over existing docetaxel containing combinations. The platelet derived growth factor receptor(PDGFR)and platelet derived growth factor (PDGF) A are frequently expressed (80%) in primary and bone marrow metastasis of human prostate cancer (PC). Recent experimental evidence suggests that activation of PDGFR/PDGF can be oncogenic in the development and/or progression of PC. There is also evidence that PC cells that express PDGF promote PDGFR expression in endothelial cells and neo- angiogenesis. Together, these experimental evidence supports that inhibition of PDGFR may be of therapeutic benefit to advanced prostate cancer patients. Gleevec (Imatinib mesylate ) is a potent inhibitor of PDGFR. Consistent with these observations, treatment with Gleevec in an experimental prostate cancer mouse model was better than paclitaxel alone in reducing bone metastasis but the antitumor effect was strongest with the combination of both. In a phase I study of heavily pretreated hormone refractory PC patients, Gleevec 600 mg/daily lead-in for 30 days followed by Gleevec 600 mg/daily with Paclitaxel 30mg/m2 weekly x4 weeks every 6 weeks induced a \>50% PSA decline in 7% and 38% of patients respectively with acceptable toxicity. These observations suggested that this combination merits further investigation. With high-dose docetaxel (70mg/m\^2) being the single most active agent in hormone refractory prostate cancer and no data existing in the use of high-docetaxel with Gleevec, a phase I/II study to determine the maximum tolerated dose (MTD) of the combination and optimum dose for a phase II trial is warranted. Gleevec is expected to affect the activation status of sensitive receptor tyrosine kinase targets and associated signaling effectors in the tumor cells and the neovasculature. However, it is not fully established to what extent alterations of the target and /or other molecules in the signaling pathway are essential for Gleevec's antitumor activity in prostate cancer patients. It is also unknown whether preexisting molecular changes in the prostate tumors of individual patients could affect Gleevec's activity even in the presence of the targets. Therefore, an assessment of the expression levels and/or presence of mutations of selected molecules in specimens of patients in clinical trials may contribute in various ways: 1. to understand the requirements to elicit or inhibit a response to the combination, 2. whether adding other targeted agents may improve response and/or 3. whether selection of patients that might benefit should be based on the tumor profile. Thus, whenever possible specimens form the primary and/or metastatic sites should be retrieved and/or obtained to perform these analyses.