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 genomic profiles of patients with CaP to tailor an individualized treatment plan. We are extensively involved in the efforts to understand the biology and genetics 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 development and progression. 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). Compelling and long-standing data suggest that androgens play an important role in the development of both normal prostate epithelium and prostate cancer. Although testosterone administration can induce prostate cancer in laboratory animals, serum-based epidemiologic studies examining androgens in humans have not consistently supported a role for androgens in prostate carcinogenesis. Since prostate cancer is highly influenced by androgens and genes, we investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. A nested case-control study from the PCPT was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. There were significant associations of genetic polymorphisms in steroid 5alpha-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend .05) were significantly associated with both circulating hormone levels and prostate cancer risk. Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Metabolism and transport play major roles in lifelong exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. While no relation to risk was found, several associations were noted between CPPC prognosis and transporters that regulate bodily sterol and fatty-acid disposition. Three SNPs in the major bile-flow transporters were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171 (bile salt export pump; p = 0.003; hazard ratio [HR]: 0.307), GSTP1 rs1799811 (glutathione S-transferase pi; p = 0.001; HR: 0.254) and SLC5A6rs1395 (sodium dependent-vitamin transporter; p = 0.004; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387 (phosphatidyl-choline floppase, MDR3; p = 0.039) and ABCC5 rs939339 (p = 0.018). This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis. 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.
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