# CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $283,247

## Abstract

Summary
Androgen deprivation therapy (ADT), with medical or surgical castration, is the long-standing frontline treatment
for advanced prostate cancer. Phase 3 trials show a profound survival benefit for addition of 1 of 4 agents
(abiraterone, docetaxel, enzalutamide or apalutamide) to intensify treatment with ADT. Unfortunately, drug
resistance eventually occurs, and disease almost always progresses as lethal castration-resistant prostate
cancer (CRPC). Regeneration of potent androgens that stimulate the androgen receptor (AR) is a major driver
of resistance, as is evidenced by the survival benefit conferred by blocking androgen synthesis (e.g., CYP17A1
inhibition) or directly blocking AR with potent antagonists. 5α-dihydrotestosterone (DHT) is the major androgen
that binds AR, and clinical studies of CRPC have consistently shown that intratumoral DHT is elevated to
physiologically relevant levels. Genetic clinical evidence now demonstrates a clear role for 3β-hydroxysteroid
dehydrogenase-1 (3βHSD1) in treatment resistance. The regeneration of DHT during ADT is due to intratumoral
androgen synthesis from precursors that may originate via de novo steroidogenesis from cholesterol or utilization
of adrenal precursor steroids. There are at least 3 possible pathways to DHT synthesis which all require
CYP17A1 - the pharmacologic target of abiraterone. No biochemical pathway of androgen synthesis is
known to circumvent this requirement for CYP17A1. Further, all pathways for the synthesis of
testosterone (T) and/or DHT require 3βHSD enzymatic activity. Clinical data from > 800 patients showing
that a genetically hyperactive form of 3βHSD1 is associated with resistance to CYP17A1 inhibition led us to
pursue the possibility that a CYP17A1-independent pathway exists that bypasses next-generation hormonal
therapy blockade. We have identified an oxysterol that prostate cancer uses as a substrate for androgen
generation via a pathway that is impervious to CYP17A1 inhibition. In contrast, this same pathway is
blocked by 3βHSD1 inhibition. Our further data suggest that 3βHSD1 phosphorylation is absolutely essential for
enzymatic activation. We propose to determine the role of alternative steroidogenesis pathways that utilize
3βHSD1, thus circumventing the requirement for CYP17A1 and enabling resistance to next-generation hormonal
therapies. We will determine the role of CYP17A1-independent androgen synthesis in next-generation anti-
androgen therapy resistance. Furthermore, we will identify and exploit phosphorylation sites that are required for
3βHSD1-dependent and CYP17A1-independent androgen synthesis. Impact: Prostate cancer is the second
leading cause of cancer death in U.S. men. Our studies will pave the way to mapping out an entirely new
biochemical pathway of androgen synthesis that will define a major mechanism of treatment resistance and new
targets for therapy. Our work is highly innovative because this pathway is entirely novel, and we will identify...

## Key facts

- **NIH application ID:** 10842022
- **Project number:** 7R01CA261995-03
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Nima Sharifi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $283,247
- **Award type:** 7
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842022

## Citation

> US National Institutes of Health, RePORTER application 10842022, CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy (7R01CA261995-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842022. Licensed CC0.

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