Background: A major problem in the treatment of advanced prostate cancer is not that we have ineffective treatments, but that these treatments eventually lose effect. Prostate cancer that has spread beyond the prostate is only temporarily controlled with lowering testosterone through surgical or medical castration, secondary to the development tumor resistance mechanisms. Patients with such hormone-resistant prostate cancer (HRPC) quickly become resistant to chemotherapy. One of our best regiments for the treatment of prostate cancer is the combination of estramustine and taxotere, which controls the tumor in over 60' of patients, but for only 6 months. In order to overcome this tendency for tumors to develop resistance, we developed a preclinical cell line model to dissect out important mechanisms of resistance including the expression of a protein that makes a cell resistant called bcl-2. In this cell model, which contains excessive bcl-2, we found that the agents 13-cis retinoic acid (a derivative of vitamin A) and alpha interferon were capable of overcoming bcl-2 resistance. We hypothesized that drugs that could overcome bcl-2 resistance would improve chemotherapy response or duration of response. We then translated these results to the clinic in a series of clinical trials, including a pilot clinical trial using the retinoid and interferon alone in patients with prostate cancer and a safety trial using these agents with taxol chemotherapy. We found that the regimen was effective in some patients and found that it caused a decrease in the bcl-2 protein in the blood of patients. We are now completing a trial on the national level using the regimen of retinoid, interferon, and taxol to determine if we can improve the response or duration of response of taxol.

Objective/Hypothesis: Given recent studies demonstrating that the combination of estramustine and taxotere (ET) may have increased response against HRPC in the clinic over taxol but is limited by a median duration of response of only 6 months, we hypothesized that retinoid and interferon will improve the response rate, or duration of response, of ET in patients with HRPC.

Specific Aims: (1) To conduct a Phase I/II trial of 13 cis retinoic acid and interferon with taxotere and estramustine (R.I.T.E) in patients with HRPC to determine the maximal tolerated dose, clinical response, and duration of response. (2) To determine the effect of R.I.T.E therapy on bcl-2 in PBMCs and tumor.

Study Design: We will treat patients with HRPC with R.I.T.E. therapy in a Phase I and II trial. We will assess bcl-2 expression as a biological marker of effect in PBMCs and in tumor in patients, as we have done in our initial studies.

Relevance: The use of estramustine and taxotere against HRPC is limited by a short duration of response in patients, secondary to the development of tumor resistance. In fact, all chemotherapy regimens used in prostate cancer, after hormonal therapy fails, last less than an average of 6 months. The problem then is not getting control with new agents, but maintaining control. Since retinoid and interferon can overcome some important mechanisms of tumor resistance in the laboratory, the addition of these agents to the estramustine/taxotore combination may improve response rate or duration of response. This would then have a profound impact on our ability to prolong control of prostate cancer. Efforts such as this may be critical, since tumors are very unstable and develop resistance to any known agent. Even new agents with greater response may require additional agents such as retinoids and/or interferon to maintain effect. This program will help our understanding of such a approach that could add to any of the research efforts that discover new agents in HRPC.