Androgen is required to regulate (i.e. balance) both the rate of proliferation and death of androgen dependent and sensitive normal prostatic epithelial cells. This regulation is via transcriptional control involving the ligand occupied androgen receptor (AR) complex. In prostate cancer cells, regulation by the ligand/AR axis is modified such that excess malignant cell growth continuously occur. During the last 4 years, a series of unique xenografts and molecular biology methods were used to document that the androgen regulation of proliferation and death of normal prostatic epithelial cells involves a paracrine dependence on prostate stromal cells. During the progression of prostate cancer, there are changes within the AR axis which result in the conversion from a paracrine dependence upon stromal cells o a direct autocrine mechanism for the regulation of proliferation and death of metastatic prostate cancer cells. This autocrine-dependent AR axis in malignant cells involves either ligand-dependent or ligand-independent pathways. presently, LHRH analogs effectively lower the serum testosterone level (i.e. androgen ablation) to activate the apoptotic elimination of the ligand (i.e. androgen) dependent prostate cancer cells within a metastatic patient. Such androgen ablation does not eliminate either the androgen sensitive or independent prostate cancer cells also present. While these cells are not dependent upon androgen for survival, their survival is dependent upon the continued expression of unoccupied AR. Geldanamycin binds to the Heat Shock 90 protein (HSP-90) when it is bound to unoccupied AR. Such binding enhances the degradation of the AR protein and thus the apoptotic death of these AR dependent prostatic cancer cells. Since geldanamycin is too toxic for systemic delivery, we purpose to chemically modify geldanamycin to produce a primary amine containing analog (Specific Aim 1). This analog will be covalently coupled via peptide bond to specific peptides to produce prodrugs. These peptide prodrugs will be designed so that they are substrates for the enzymatic activity of either Prostate Specific Antigen.
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