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

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $374,728

## Abstract

Project Summary
 Prostate cancer depends on androgens and the androgen receptor (AR) for growth and progression.
Metastatic tumors are usually initially treated with androgen deprivation therapy (ADT) by way of medical or
surgical castration; however, tumors eventually recur as castration-resistant prostate cancer (CRPC), which
progresses due to the intratumoral generation of testosterone and/or dihydrotestosterone (DHT) and AR
stimulation. The intratumoral synthesis of potent androgens requires the activity of steroidogenic enzymes. In
the prior project period, we identified the first example of a gain-of-function missense in a steroidogenic enzyme
that increases what is otherwise the rate-limiting step of DHT synthesis from extragonadal precursor steroids and
spurs the development of CRPC. This missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) is encoded by
HSD3B1(1245C), a common germline variant. In the prior project period, we also discovered that patients with
advanced prostate cancer who inherit the HSD3B1(1245C) genetic variant and receive ADT progress to CRPC
more rapidly than patients who inherit the wild-type HSD3B1 enzyme, which has lower activity. Although
clinical data across 4 patient cohorts now show that the HSD3B1(1245C) genetic variant is a predictive biomarker
of resistance to ADT, the precise clinical utility of this biomarker remains uncertain. The overarching goal of
this proposal is to determine how HSD3B1(1245C) should be utilized as a biomarker to identify patients who
require more intensive upfront treatment and who are otherwise likely to progress more rapidly to lethal disease.
 As the HSD3B1(1245C) variant encodes for an enzyme that enables more rapid conversion of
extragonadal precursors to DHT, we hypothesize that HSD3B1(1245C) is a predictive biomarker of sensitivity to
drugs that block the synthesis or effects extragonadal androgens. We hypothesize that metabolism by 3βHSD1
is a class effect of steroidal CYP17A1 inhibitors, thus making non-steroidal CYP17A1 inhibitors or potent AR
antagonists more suitable for treating patients who harbor the HSD3B1(1245C) variant. Finally, we hypothesize
that intensification of treatment at the time of ADT in phase III clinical trials improves outcomes for patients with
metastatic prostate cancer who inherit the HSD3B1(1245C) variant. In Aim 1, we will determine if inheritance
of the HSD3B1(1245C) variant is a predictive biomarker of response to non-steroidal CYP17A1 inhibitors or
potent AR antagonists. In Aim 2, we will identify whether susceptibility to 3βHSD metabolism is a class effect
of steroidal CYP17A1 inhibitors and how this may determine response for patients who inherit the HSD3B1
variant. In Aim 3, we will determine if patients with prostate cancer who inherit the HSD3B1(1245C) variant
specifically benefit from more intensive upfront treatment at the time of ADT. If we are correct, the work in this
proposal will change standard clinical practice for the treatmen...

## Key facts

- **NIH application ID:** 10372921
- **Project number:** 5R01CA172382-10
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Nima Sharifi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,728
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372921

## Citation

> US National Institutes of Health, RePORTER application 10372921, Elucidating a novel molecular biomarker for castration-resistant prostate cancer (5R01CA172382-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10372921. Licensed CC0.

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