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 use a candidate gene approach which uses a panel of 96 SNPs (identified from prior studies and published literature) from over thirty genes and using DNA samples from subjects with metastatic disease or without biochemical recurrence for over 5 years after treatment. Constitutional DNA from men who were biochemical recurrence free after treatment of their CaP identified from the San Antonio center for Biomarkers Of risk for prostate cancer (SABOR) are being provided by our research collaborator, Dr. Robin Leach. These samples are compared to the constitutional DNA from men with documented metastatic prostate cancer identified from patients treated at the NCI. Preliminary findings revealed that 5 SNPs are statistically significant different between men with metastatic disease and those without. Two SNPs, rs1544410 and rs2254210, found in the vitamin D receptor gene locus appeared to be protective against metastatic disease. Three SNPs found in genes for MSR1, osteoprotegerin, and ERG (rs3789015, rs2073617, rs2836582;respectively) appeared to increase the risk of metastatic disease. Future experiments will identify more important SNPs and focus on biochemical and molecular biological testing of the identified important genes. 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. We completed a study on 321 primary tissue samples from 21 normal and cancerous patients that examined the expression of 3 family members implicated in cancer: OATP1B3, OATP1B1 and OATP2B1. OATP2B1 is more ubiquitously expressed in all tissues than OATP1B1 and OATP1B3. OATP1B3 is expressed in fewer normal tissue types but was expressed in 50% of cancerous samples with a trend of increasing OATP1B3 expression with a higher Gleason score. This supports previous data suggesting a role for OATP1B3 in prostate cancer progression. Experiments from quantitative PCR and Western analysis suggest that hypoxia response elements in the OATP1B3 promoter are activated under hypoxic conditions, identify HIF-1alpha mediated regulation that contributes to the increased expression in tumor cells. Transport studies in Xenopus oocytes showed that optimal transport occurs at low androgen levels such as those seen in patients after androgen deprivation therapy. Future studies will characterize the role of OATP1B3, OATP1B1 and OATP2B1 as potential candidate biomarkers for tumor progression in several cancers. 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 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 and found no association of AR CAG repeat length with CaP risk. We found that low post-treatment serum estrogens may identify men more likely to benefit from use of finasteride to prevent prostate cancer. We have recently shown that the estrogen receptor (ER)-alpha and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with CRPC treated with docetaxel-based therapy. We found that estrogen-related genetic variation affects docetaxel clinical response that is dependent on age and body-type in men with CRPC. This study suggests ER-alpha polymorphisms confer risk of developing CaP, especially in men under 70 years of age. Racial disparities in the association between variants on 8q24 and prostate cancer: 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.
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