# Project 4: Identification of Essential Genes Underlying AR Activity in Antagonist-Resistant CRPC

> **NIH NIH P01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $341,767

## Abstract

The mechanisms underlying prostate cancer progression from androgen dependent to castration resistant
prostate cancer (CRPC), as well as those mediating resistance to therapies that target the residual androgen
receptor (AR) signaling in CRPC including second generation AR antagonists such as enzalutamide have not
been fully elucidated. Work from several groups including our own has highlighted the continued dependence
of CRPC on AR and has implicated EZH2 as an additional oncogenic driver involved in AR reprogramming in
CRPC. In studies accomplished during the current funding period we have explored EZH2 as a target in
models of CRPC and have demonstrated that catalytic EZH2 inhibitors have activity in these models. The goal
of this proposal is to leverage the novel genome-scale CRISPR/Cas9 and ORF screening technology to
identify the essential genes and their functions that underlie the hormone independence and sensitivity or
resistance to EZH2 inhibitors, AR antagonists, and other targeted agents in CRPC. In addition, in collaboration
with the Freedman lab we will use CRISPR/Cas9 editing of cis-regulatory elements to explore in detail the
function of a novel somatically acquired transcriptional enhancer in controlling the expression of the AR gene
itself in CRPC. We will also define the essential genes in models of CRPC driven by ARv7 and other AR
mutants and variants in collaboration with Project 2. Finally, we will perform CRISPR and ORF screens to
identify potential new synthetic lethal combinations and mechanisms of resistance including to a set of novel
kinase inhibitors in collaboration with the Project 3.

## Key facts

- **NIH application ID:** 9870890
- **Project number:** 5P01CA163227-07
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** MYLES A BROWN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $341,767
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870890

## Citation

> US National Institutes of Health, RePORTER application 9870890, Project 4: Identification of Essential Genes Underlying AR Activity in Antagonist-Resistant CRPC (5P01CA163227-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9870890. Licensed CC0.

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