Prostate cancer (PC) is the most commonly diagnosed form of cancer in U.S. males. This year 99,000 new cases will be diagnosed. Approximately 1 in 10 to 12 American males will develop clinical PC during their lifetime and there will be approximately 30,000 PC deaths this year alone. Metastatic prostatic cancer is a fatal disease for which no therapy is available which effectively increases survival. The major reason for the inability of androgen ablation monotherapy to increase survival in men with metastatic prostatic cancer is that the cancer within individual patients is heterogeneously composed of clones of both androgen dependent and independent prostatic cancer cells even before therapy is initiated. Thus, androgen ablation does no affect the pre-existing androgen independent cancer cell already present. What is desperately needed, therefore, is an effective therapy for the pre-existing androgen independent prostatic cancer cells which can be combined with any of a large variety of presently available forms of androgen ablation thus affecting all of tumor cell population present within the heterogeneous cancer. The goal of the proposed studies is to develop new therapeutic approaches to control androgen independent prostatic cancer cells other than the current chemotherapies using drugs designed to block rapidly proliferating cancer cells, since these therapies have proven ineffective in controlling slow growing prostatic cancers. Since the growth of a cancer is determined not only by the rate of cell proliferation but also by the rate of cell death, attempts are being focused upon developing methods of increasing the rate of cell death, specific in Go prostatic cancer cells. To do this advantage is taken of the fact that in the normal prostate large numbers of Go prostatic cells can be induced reproducibly to die by androgen ablation and that this process of cell death occurs as a programmed series of temporally discreet biochemical steps. The long term goal of the PI is to develop some type of non-androgen ablation method to activate this programmed cell death cascade in androgen independent prostatic cancer cells distal to the point of the defect. In order to have any realistic change of success, a great deal of additional basic information will have to be obtained. Therefore, the PI proposes to initiate a series of very basic but fundamental questions concerning the programmed cell death process in normal and malignant prostatic cells.
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