# New Treatment Strategies and Epigenetic Biomarker for Management of BPH

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $598,609

## Abstract

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.

## Key facts

- **NIH application ID:** 11062157
- **Project number:** 1R01DK142211-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Aria F Olumi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,609
- **Award type:** 1
- **Project period:** 2024-09-20 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11062157

## Citation

> US National Institutes of Health, RePORTER application 11062157, New Treatment Strategies and Epigenetic Biomarker for Management of BPH (1R01DK142211-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11062157. Licensed CC0.

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