Gary R Hudes, MD
Our primary goal is to develop more effective treatment for advanced prostate cancer, a disease responsible for 40,000 deaths annually. We have performed a series of clinical trials based on the hypothesis that drugs with complementary targets within the microtubule complex of cells can be combined to produce more effective prostate cancer treatment. In support of this hypothesis, our previous studies have demonstrated that combinations of estramustine with either paclitaxel or vinblastine produce regression of metastases in approximately half of patients with hormonally-resistant prostate cancer (HRPC). Our current efforts are aimed at improving the extent and duration of tumor regression, and reducing the toxic effects of treatment. In two recently completed studies, we have shown that 1) intravenous (i.v.) estramustine can be administered safely at doses much higher than were previously thought possible, and 2) weekly administration of paclitaxel with reduced, intermittent doses of oral estramustine is better tolerated and at least as effective as the more cumbersome and toxic continuous administration of estramustine and paclitaxel.
To build upon these encouraging results, it will be necessary to identify new drugs that block prostate cancer growth and that can be added to our current combination therapies without causing excessive toxicity. In the past year, we have completed a phase I clinical trial of R115777, an orally administered methylquinone and potent inhibitor of the enzyme, farnesyl protein transferase (FPTase). Importantly, we have seen antitumor effects in patients with HRPC, thus making R115777 and other inhibitors of FPTase logical candidates for further study in patients with HRPC.
A premise of our research program is that progress in the chemotherapy of prostate cancer and other malignancies will depend on rational incorporation of agents that modify cell signaling and gene expression in a manner that promotes programmed cell death, modulates stress response, or modifies cell cycle progression to enhance the actions of traditional cytotoxic drugs.