We are conducting translational research to develop new agents and/or therapeutic maneuvers that appear to have antitumor activity in prostate cancer (CaP), and to develop molecular profiles of patients with CaP to tailor an individualized treatment plan. We are extensively involved in the efforts to understand the biology of CaP and to correlate biological variables associated with CaP and response to therapy. We reported the first confirmation of the therapeutic efficacy of flutamide withdrawal and 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. We have analyzed candidate genes at the genomic level for genetic variations that may predispose individuals to increased risk of prostate cancer. Biomarker discovery for CaP is an ongoing effort in our laboratory and we have focused on the identification of single nucleotide polymorphisms (SNPs) involved in CaP progression. We investigated racial disparities in the association between variants on 8q24 and prostate cancer and demonstrated that recent studies implicate SNPs within the 8q24 region as a risk factor for CaP. New developments suggest that 8q24 encodes regulators of the nearby MYC gene, a known oncogene. We performed meta-analyses, stratified by race, of seven SNPs and one microsatellite marker previously identified as risk loci on the 8q24 region of the genome. We reviewed the literature examining the possible associations between these polymorphisms and clinicopathological features of CaP. The results of the meta-analyses indicate that rs6983267, rs1447295, rs6983561, rs7837688, rs16901979, and DG8S737 are significantly associated with a higher risk for CaP for at least one race, whereas the variants rs13254738 and rs7000448 are not. The degree of association and frequency of the causative allele varied among men of different races. Though several studies have demonstrated an association between certain 8q24 SNPs and clinicopathological features of the disease, review of this topic revealed conflicting results. We are also interested in understanding the molecular genetics of androgen transport. The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. We have shown that prostate cancer overexpresses OATP1B3 compared to normal or benign hyperplastic tissue, and the common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with CaP. We found that a polymorphism in this transporter increases testosterone import is associated with a shorter time to androgen independence in patients with CaP who are treated with ADT. Studies are ongoing to characterize the mechanisms of androgen transport and whether the genetics of the OATP1B3 transporter influences the outcome of prostate cancer patients on androgen deprivation therapy. The Prostate Cancer Prevention Trial (PCPT) investigated the prevention of prostate cancer using the steroid 5 alpha-reductase inhibitor finasteride over a 7-year treatment period. Through a longstanding collaboration, we have access to the tissue samples of 18,800 men enrolled in this study. The overall goals of this project are: a) to better understand associations between important androgen regulatory gene polymorphisms and CaP risk; and b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for CaP. Our focus is on hormone-related factors that are associated with cancer risk, which may help explain the findings of the PCPT (i.e., decreased overall occurrence of adenocarcinoma, but increased prevalence of high-grade disease in the finasteride treatment arm). We hypothesized that men with polymorphisms within genes that positively impact androgen levels will have a higher risk of developing CaP and high-grade disease than those with the wild-type alleles. Long-term exposure to finasteride may select for somatic alterations and increase serum levels of testosterone and potentially harmful testosterone breakdown products. Evaluation of whether the polymorphic variations in the AR, SRD5A2 and HSD3B2 genes are associated with the risk of biopsy-detected CaP in the PCPT is underway. We identified, by laser-capture microdissection and direct nucleotide sequencing, somatic alterations in AR and HSD3B2 that may have been selected for by long-term exposure to finasteride. We are also determining whether prostate cancer somatic mutations of these genes differ with regard to their prevalence between the placebo and finasteride arms, and among PIA, HGPIN, prostate cancer and normal epithelium. These findings will help define a pharmacogenomic profile to identify men that are most likely to benefit from treatment with 5 alpha-reductase inhibitors. We also examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations. Among men with detectable finasteride concentrations, there was no association between finasteride concentrations and prostate cancer risk, low-grade or high-grade, when finasteride concentration was analyzed as a continuous variable or categorized by cutoff points. Since there was no concentration-dependent effect on prostate cancer, any exposure to finasteride intake may reduce prostate cancer risk. Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway. We further investigated the association between the length of the polymorphic trinucleotide CAG microsatellite repeats in exon 1 of the AR gene and the risk of prostate cancer containing TMPRSS2:ETS fusion genes. There was no association between the CAG repeat length and the risk of TMPRSS2:ETS-positive (odds ratio, 0.97; 95% confidence interval, 0.91-1.04) or TMPRSS2:ETS-negative prostate cancer (odds ratio, 1.04; 95% confidence interval, 0.97-1.11) and in patients with low- or high-grade disease. Our findings suggested that AR CAG repeats are not associated with TMPRSS2:ETS formation in prostate cancer.
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