# Notch-mediated 5ARI resistance in human BPH

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $373,504

## Abstract

Summary
 Alpha adrenergic receptor blockers (α-blockers) are a first line therapy for relaxing muscle tension to improve
voiding in patients with lower urinary tract symptoms (LUTS), but are most effective on smaller, non-fibrotic
prostates. Steroid 5a-reductase inhibitors (5ARI) block the local production of dihydrotestosterone (DHT),
representing the only therapy for shrinking prostate volume through apoptosis of luminal epithelia. Combining
both of these therapies is expensive, has unwanted side effects, and fails to fully slow the risk of symptomatic
progression. These data suggest that we have yet to target the variety of pathogeneses regulating BPH
progression.
 Understanding the molecular pathogenesis of 5ARI resistance is a High-Priority Recommendation of the
NIDDK Strategic Plan for Prostate Research. The potential links between variable drug response and
histopathological features are poorly studied. We present an innovative approach to deconstructing the
molecular pathogenesis of a prevalent 5ARI resistant phenotype: the glandular nodule.
 The conflicting data on the pathogenesis of BPH is largely due to a lack of comprehensive translational
human tissue studies that account for heterogeneity by binning specimens into histopathological categories. We
focus here on a glandular nodule phenotype observable in ~60% of our patients and demonstrate two key points
in our preliminary data: 1) LC-MS/MS of androgen and 5ARI levels in patients revealed that 5ARIs are functioning
to reduce DHT in nodules, but are failing to induce luminal epithelial apoptosis, suggesting 5ARI resistance; and
2) RNA-seq of luminal epithelia from 5ARI resistant nodules shows elevated Notch pathway activity. We will test
the hypothesis that luminal epithelial Notch signaling drives 5ARI-resistant nodule formation in human BPH with
three critical pieces of evidence: 1) MRI will be sequentially performed on patients before and after 5ARI
treatment to identify whether glandular nodules regress; 2) nodular surgical specimens from 5ARI-resistant
patients will be examined by LC-MS/MS and histopathology for correlating DHT independence with Notch
activity; and 3) glandular nodule explants and transgenic animals with ectopic Notch activation will be treated to
determine whether Notch inhibition sensitizes the prostate to 5ARI treatment. Successful completion of our aims
will establish a molecular and phenotypic classification of 5ARI-resistance and a clinical tool for non-invasive
discrimination of patients with 5ARI-resistant glandular nodules.
Relevance
New insight into how BPH patients fail 5ARI therapy holds great promise for identifying novel approaches to
medical therapy in the treatment of BPH.

## Key facts

- **NIH application ID:** 10413136
- **Project number:** 5R01DK115477-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Douglas William Strand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $373,504
- **Award type:** 5
- **Project period:** 2018-07-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413136

## Citation

> US National Institutes of Health, RePORTER application 10413136, Notch-mediated 5ARI resistance in human BPH (5R01DK115477-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10413136. Licensed CC0.

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