# Elucidating a novel molecular biomarker for castration-resistant prostate cancer

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $401,019

## Abstract

SUMMARY
Prostate cancer is the second leading cause of cancer death in U.S. men. The frontline treatment for advanced
prostate cancer is androgen deprivation therapy (ADT), which has been the standard of care for ~80 years. Recent
practice-changing data have demonstrated a survival benefit when ADT is intensified, but the treatment choice
for intensification is unclear. Regardless, metastatic disease almost always progresses as castration-resistant
prostate cancer (CRPC). A major limitation of new CRPC treatments is that patients are selected based on prior
therapies instead of their genetics and disease-driving molecular processes. Essential findings from our previous
project period include clear and reproducible clinical evidence that an “adrenal-permissive” HSD3B1(1245C)
germline variant encodes for a gain-of-function missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1),
the rate-limiting steroidogenic enzyme for synthesis of 5α-dihydrotestosterone (DHT) from extragonadal
precursor steroids. This adrenal-permissive HSD3B1 is a genetic and metabolic driver of hormone therapy
resistance. In this renewal application, we propose to determine the mechanisms and clinical significance of
inheritance of the HSD3B1(1245C) variant and move toward its use as a biomarker to tailor castration-
resistant and castration-sensitive prostate cancer treatment to the individual patient's genetics and tumor
biology. We hypothesize that the germline HSD3B1(1245C) variant is a predictive biomarker that will allow us
to identify patients who will benefit from upfront adrenal androgen ablation. Our preliminary data indicate that
BMX inhibition of 3βHSD1 phosphorylation will be therapeutic – direct therapeutic inhibition of 3βHSD1 for
men with the adrenal-permissive HSD3B1 should reverse the adverse biology and clinical outcomes conferred by
extragonadal androgen biosynthesis in CRPC. Our data also indicate that after intensified hormonal therapy,
HSD3B1 inheritance is a determinant of systemic metabolic effects, including adverse effects seen in some men,
but not others. The potential clinical consequences of the concepts we propose are profound because they
couple a germline disease-driving metabolic driver to therapeutic mechanisms for reversal of poor outcomes.
Aim 1: Determine whether inheritance of the adrenal-permissive HSD3B1(1245C) allele is a predictive
biomarker of improved benefit from adding abiraterone to ADT for non-metastatic castration-sensitive prostate
cancer. We will analyze germline DNA available from 959 men enrolled in the STAMPEDE trial. Aim 2: Define
the role of phosphorylation in 3βHSD1 activation and determine the role of BMX in the conversion of DHEA to
downstream potent androgens. We will determine if the BMX kinase is essential for 3βHSD1 phosphorylation
and cellular activation and test its efficacy in a proof-of-concept clinical trial. Aim 3: Determine the mechanistic
link between HSD3B1 inheritance and circulating metabolites in men un...

## Key facts

- **NIH application ID:** 10911921
- **Project number:** 5R01CA172382-12
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Nima Sharifi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,019
- **Award type:** 5
- **Project period:** 2012-09-26 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911921

## Citation

> US National Institutes of Health, RePORTER application 10911921, Elucidating a novel molecular biomarker for castration-resistant prostate cancer (5R01CA172382-12). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10911921. Licensed CC0.

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