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. 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., mutated androgen receptor, CAG repeats and microvessel count). The Molecular Pharmacology Section reported 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. Whether this phenomenon is unique to the LNCaP cell line or is also responsible for the observations made in vivo is unknown. This question is being actively pursued in our section. More recently, we have initiated experiments in an attempt to determine which genes are regulated by the androgen receptor. In particular, we are interested in a polymorphism in the AR (a trinucleotide repeat in exon 1 -- CAG repeat). We are interested in analyzing several candidate genes at the genomic level for genetic variations that may predispose individuals to increased risk of prostate cancer. All of the genes listed below have shown preliminary evidence that suggests that they may play important roles. Genes involved in the natural production of endostatin (COL18A1), the enzymes involved in testosterone processing (SRD5A1&2), drug metabolism (CYP3A4 &5), and genes involved in cellular transport and conjugation (UGT1A1, UGT2B15, UGT2B17) are being investigated for their involvement in the onset, progression and metastasis of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010453-01
Application #
6753253
Study Section
(MPCT)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Figg, William D; Chau, Cindy H; Price, Douglas K et al. (2014) Androgen receptor CAG repeat length and TMPRSS2:ETS prostate cancer risk: results From the Prostate Cancer Prevention Trial. Urology 84:127-31
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Sharifi, Nima; Dahut, William L; Figg, William D (2008) The genetics of castration-resistant prostate cancer: what can the germline tell us? Clin Cancer Res 14:4691-3
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Sissung, Tristan M; Price, Douglas K; Sparreboom, Alex et al. (2006) Pharmacogenetics and regulation of human cytochrome P450 1B1: implications in hormone-mediated tumor metabolism and a novel target for therapeutic intervention. Mol Cancer Res 4:135-50
Sissung, Tristan M; Mross, Klaus; Steinberg, Seth M et al. (2006) Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer 42:2893-6
Chau, Cindy H; Figg, William D (2005) Molecular and phenotypic heterogeneity of metastatic prostate cancer. Cancer Biol Ther 4:166-7

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