Genetics and Molecular Mechanisms of Prostate Cancer

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We have conducted translational research to understand the genetic and molecular mechanism that govern prostate cancer development and progression, to identify novel pathways for drug development, and investigate mechanisms of resistance to treatment paradigms. We have a longstanding collaboration with the Prostate Cancer Prevention Trial (PCPT) investigators to elucidate the molecular and genetic mechanisms that may help explain the trial outcomes of the PCPT. 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. We recently determined that associations between SNVs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment. The FDA recently approved two PARP inhibitors, olaparib and rucaparib, for treatment of biomarker-positive metastatic castrate resistant prostate cancer (mCRPC). The benefits of PARP inhibition have been well characterized in patients that have BRCA1 and BRCA2 mutations in several forms of cancer. BRCA1 and BRCA2 occupy key roles in DNA damage repair, which is comprised of several different pathways with numerous participants. Patients with mutations in other key genes within the DNA damage repair pathway may also respond to treatment with PARP inhibitors, and identification of these alterations could significantly increase the percentage of patients that may benefit from PARP inhibition. Our most recent genetic study (in collaborative effort among several institutions including the Center for Prostate Disease Research) found that increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population. Germline mutations in BRCA2 have been linked to a higher risk of prostate cancer, and high frequency of BRCA1 and BRCA2 (BRCA1/2) gene alterations was recently reported in mCRPC specimens. Mutations in BRCA2 vary in racial and ethnic groups including African-American (AA) and Caucasian-American (CA) populations. BRCA1 and BRCA2 genes were sequenced (Ion AmpliSeq targeted sequencing) in archived blood DNA specimens in 1240 PCa patients, including 30% AA patients, in three different cohorts: localized early stage (T2) PCa (N = 935); advanced PCa (50% T3-4) (N = 189); and metastatic PCa (N = 116). The sequences were analyzed for known and novel mutations in BRCA1/2. Statistical analyses were performed to determine associations of the mutations with clinico-pathological parameters. BRCA2 mutations with known pathogenic annotation were significantly more prevalent in men with advanced and metastatic PCa (3.1%) compared to patients with an organ-confined disease (0.7%). AA patients carried more frequently BRCA1/2 variants of unknown significance (VUS) when compared to Caucasian Americans (4.6 vs. 1.6%, respectively). Significantly, pathogenic BRCA2 mutations in men with localized early stage PCa increased the risk of distant metastasis. Germline variants of unknown significance in BRCA1/2 are more frequent in AA than CA PCa patients; however, the prevalence of pathogenic mutations were similar across the races. Patients carrying BRCA2 pathogenic mutations are more likely to progress to metastasis. 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. Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. We recently conducted studies to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of OATP1B3. We found that de novo OATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival. Studies are ongoing to characterize the molecular mechanisms of SLCO1B3 transcription including transcription factor complexes that assemble at distinct regulatory elements in the SLCO1B3 promoter for driving tissue-specific expression of OATP1B3 in prostate cancer. Understanding the underlying regulatory mechanisms of OATP1B3 expression and the transporter's role in prostate cancer progression will aid in its development as a potential therapeutic target. To this end, we are currently developing an OATP1B3 inhibitor screening assay that will be validated for use in a high-throughput screening of compounds from the National Cancer Institute's Natural Products Repository.