# Chemical Epigenomic Strategies to Overcome Metastatic Castration Resistant Prostate Cancer

> **NIH NIH K22** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $175,095

## Abstract

ABSTRACT
Nuclear receptors are steroid-dependent transcription factors that confer cell identity. They guide
development, and maintain homeostasis in adult tissue, such as the testosterone responsive Androgen
Receptor which governs male-specific tissues. Aberrant AR-driven gene expression programs give rise to
prostate cancer. When resistance arises after androgen-deprivation therapy (ADT) the disease advances to
the much more lethal metastatic castration-resistant prostate cancer (mCRPC), becoming resistant to these
therapies by overexpressing AR. New evidence suggests that many other transcription factors and epigenetic
co-activator proteins may create disease-specific enhancers with the AR to drive tumors, especially in
treatment-relapsed mCRPC. As a well-trained synthetic chemist, molecular biologist and computational
biologist, I will map the epigenetic mechanisms at work in mCRPC, in new clinically relevant organoid models. I
will show how to stop the AR-axis using small molecules I discovered with novel mechanisms of action, where
the AR undergoes a chemically induced functional switch, causing the AR to suppress the tumor-driving genes
it normally activates. Additionally, I aim to uncover co-dependency epigenetic proteins which drive late stage
disease, and use new molecules perturbing CBP/p300 (histone acetyl transferases that build active enhancers)
as a strategy to selectively halt the genes driving disease relapse. At the conclusion of this work, we should
have the first mechanistic understanding the AR under the influence of an inverse agonist, provide functional
epigenetic map of regulatory addictions in advanced PCa, and have explored therapeutic potential of promising
new AR therapeutics.

## Key facts

- **NIH application ID:** 10104014
- **Project number:** 1K22CA255594-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Berkley E Gryder
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $175,095
- **Award type:** 1
- **Project period:** 2021-06-02 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104014

## Citation

> US National Institutes of Health, RePORTER application 10104014, Chemical Epigenomic Strategies to Overcome Metastatic Castration Resistant Prostate Cancer (1K22CA255594-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104014. Licensed CC0.

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