# Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $274,080

## 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 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 and AR stimulation. The identification
of these mechanisms and the requirement for sustained AR stimulation has led to the development of
enzalutamide, which is a next-generation hormonal therapy that directly and potently antagonizes AR and thereby
extends survival for men with metastatic CRPC. Unfortunately, responses to enzalutamide are temporary and
resistance eventually leads to death. Enzalutamide resistance is therefore a major and widespread clinical problem
for patients with advanced prostate cancer.
 Recent evidence suggests that enzalutamide resistance is driven by an up-regulation of the glucocorticoid
receptor (GR), which re-establishes the expression of 50% of genes that are usually responsive to AR stimulation.
Unfortunately, the clinical application of this finding is challenged by the fact that complete and systemic GR
ablation is lethal in humans. However, identification of a tumor tissue-specific mechanism that enables GR
stimulation might provide a potential therapeutic target that would not compromise the patient.
 We hypothesize that GR stimulation that occurs with AR antagonist resistance is accompanied by a
tumor-specific metabolic mechanism that furnishes abundant local concentrations of cortisol, a GR agonist. Our
preliminary data demonstrate that 11β-hydroxysteroid dehydrogenase-2 (11βHSD2), the enzyme that is primarily
responsible for cortisol inactivation, is lost with AR antagonist resistance, resulting in augmented local cortisol
concentrations. Furthermore, we hypothesize that blocking this metabolic mechanism would reverse GR
stimulation and thereby reinstate responsiveness to AR antagonist therapy. Our preliminary data suggest that
replacing 11βHSD2 enzymatic function, by either restoring 11βHSD2 expression or blocking the machinery that
is required for 11βHSD2 protein degradation, reverses the metabolic phenotype and restores sensitivity to AR
antagonist therapy. In Aim 1, we will determine the metabolic phenotype conferred by treatment with next-
generation hormonal therapies for CRPC. In Aim 2, we will identify the molecular mechanisms that regulate
glucocorticoid metabolism in AR antagonist resistance. In Aim 3, we will determine the therapeutic significance
of restoring the baseline metabolic phenotype in AR antagonist resistance. Together, these studies will identify
and clinically validate mechanisms that drive AR antagonist resistance. It is anticipated that this work will lead
to the identification of tumor-specific mechanisms of resistance to next-generation hormonal therapies that are
pharmacologi...

## Key facts

- **NIH application ID:** 10847199
- **Project number:** 7R01CA236780-05
- **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:** $274,080
- **Award type:** 7
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847199

## Citation

> US National Institutes of Health, RePORTER application 10847199, Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer (7R01CA236780-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10847199. Licensed CC0.

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