New Treatment Strategies and Epigenetic Biomarker for Management of BPH

PROJECT SUMMARY: Over 90% of adult males develop lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction by age 80 secondary to benign prostatic hyperplasia (BPH). BPH, the most common proliferative abnormality in humans, negatively impact the quality of life of 210 million men globally, accounting for significant life years lost. In this study we propose to clinically evaluate the mechanisms of resistance to 5α-reductase inhibitor, finasteride, one of the more common drugs used to manage BPH and associated LUTS. Ongoing work in our lab has focused on steroid 5α-reductase 2 (SRD5A2, aka: 5α-reductase 2 [5AR2]), the enzyme responsible for prostatic development and growth. Our investigations have revealed that expression of SRD5A2 is variable, and in fact, 30% of men do not express SRD5A2 in prostate tissues. In previous work, we showed that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Our studies indicate that (1) methylation of the SRDA2 is regulated by direct binding of the DNA-methyl transferase 1 (DNMT1) protein to the SRD5A2 promoter; (2) the inflammatory mediators TNF-α, NF-kB, and IL-6 regulate DNMT1 binding and subsequent methylation of the SRD5A2 promoter region; (3) clinical conditions associated with increased inflammation, age, and obesity, are associated with decreased expression of SRD5A via epigenetic modification; (4) in the absence of prostatic SRD5A2, alternate estrogenic pathways are upregulated, leading to an androgenic-to-estrogenic switch in the prostate gland, thus creating alternate pathways for prostatic growth. Therefore, we hypothesize that (1) non- invasive assessment of SRD5A2 methylation status in peripheral blood can be an excellent indicator for resistance to 5ARI therapy, and (2) in men demonstrating hypermethylation of SRD5A2 and low protein expression (patients suspected of being resistant to 5ARI therapy), combination therapy (Selective Estrogen Receptor Modulators [SERMs]+5ARI) will serve as a better treatment strategy. To demonstrate the clinical significance of epigenetic changes to SRD5A2 and confirm its role in regulating sensitivity to 5ARI treatment, and to examine the role of estrogenic signaling blockade, we propose a clinical trial with: Specific Aim 1: To assess the role of combination therapy (5ARI + SERM) in the treatment of BPH and to determine whether methylation of SRD5A2 promoter is a predictor for response to therapy. Specific Aim 2: To prospectively evaluate whether non-invasive radiologic prostate inflammatory markers can predict circulating WBCs SRD5A2 promoter methylation.