It is well known that androgen deprivation is the cornerstone of initial therapy for metastatic prostate cancer. Once metastatic prostate cancer progresses in the face of hormonal therapy, it is classified as being androgen independent. Therapeutic options for patients with androgen independent prostate cancer are extremely limited. In particular, cytotoxic chemotherapy has provided minimal benefit. The purpose of this project is to perform translational research to develop new agents, and/or therapeutic maneuvers, that appear to have antitumor activity in prostate cancer, and to develop molecular profiles of patients with prostate cancer to tailor an individualized treatment plan. To achieve this goal, we have become extensively involved in the efforts to understand the biology of prostate cancer. Currently, we are attempting to correlate biological variables associated with prostate cancer and response to therapy (e.g., important polymorphic markers, and microvessel counts). One early achievement by the Molecular Pharmacology Section was to report the first confirmation of the therapeutic efficacy of flutamide withdrawal, as well as the enhanced activity of simultaneous adrenal suppression. It has been hypothesized that the clinical improvement associated with flutamide is a result of the presence of a mutation within the ligand-binding domain of the androgen receptor. As we and others have reported, the human prostate cancer cell line LNCaP, which expresses such a mutated receptor, is stimulated to grow by hydroxy-flutamide, the active metabolite of flutamide. We believe that the mutation in the ligand-binding domain of the androgen receptor causes these normally antagonistic compounds to behave as androgen agonists. Work to determine whether this phenomenon is unique to the LNCaP cell line or is also responsible for the observations made in vivo is ongoing. We remain interested in analyzing candidate genes at the genomic level for genetic variations that may predispose individuals to increased risk of prostate cancer. We have completed the analysis of genes involved in the natural production of endostatin (COL18A1, no statistical difference), a gene directly involved in the synthesis of testosterone from cholesterol (CYP17, the results suggest that the polymorphism is associated with overall survival in patients with androgen independent prostate cancer), a gene involved in the toxic metabolic breakdown of testosterone (CYP1B1, an association with decreased survival was observed), drug metabolism (CYP3A4 &5, the studied genetic variants are unlikely to have an important functional significance to phenotypic CYP3A activity in patients with cancer), and a gene involved in cellular transport and conjugation (UGT1A9, functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens). Furthermore, the analysis of other genes (SRD5A1&2, LOX, CYP19, OATP1B3, ER) which have shown preliminary evidence that suggests that they may play important roles are ongoing and at various stages of completion. Other polymorphic containing genes of interest have been recently identified after screening the DNA from patients with prostate cancer against a gene chip designed to screen genes involved in metabolism and drug transport. These important genes will be added to the ongoing goal of a molecular """"""""fingerprint"""""""" of prostate cancer. Some of the overall goals of this project are: (a) to better understand associations between important androgen regulatory gene polymorphisms and prostate cancer risk and (b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for prostate cancer. The recently completed Prostate Cancer Prevention Trial (PCPT) investigated the prevention of prostate cancer using the steroid 5 alpha-reductase inhibitor finasteride over a seven year treatment period.
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