# Project 2: Targeting Emergent Vulnerabilities in AR-Inactive Prostate Cancer

> **NIH NIH P50** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $110,615

## Abstract

PROJECT SUMMARY/ABSTRACT
Treatment options for patients with castration-resistant prostate cancer (CRPC) are expanding. However, 27,000
men will still die from this disease in 2017. We and others have found that widespread use of novel and more
potent androgen receptor (AR)-targeting agents has increased the clinical frequency of virulent and untreatable
AR-independent CRPC subsets. These subsets include: AR-indifferent prostate cancer (AIPC) with persistent
AR expression but reduced AR function, neuroendocrine prostate cancer (NEPC), and AR-null tumors without
neuroendocrine differentiation that we have termed double-negative prostate cancer (DNPC). However, very
little is known about what factors promote the transition to and maintenance of specific AR-independent subsets.
Furthermore, there are no effective treatments for patients with these tumors. The goal of this proposal is to
overcome those deficits. Our studies using human AIPC, NEPC, and DNPC patient tumors and model systems
identified specific transcriptional regulators, including BET bromodomain chromatin reader proteins, Master
Regulator transcription factors (TFs), and kinases that are activated in AIPC, NEPC, and DNPC. In this proposal,
we will test the overarching hypothesis that gene networks regulated by BET bromodomain proteins, aberrantly
activated TFs or kinases, and other key signaling pathways promote AR-independent CRPC cell survival. We
propose the following Aims:
Aim 1: Determine the anti-tumor activity of the BET bromodomain inhibitor ZEN-3694 in patients with AR-
 independent CRPC.
Aim 2: Identify and target critical Master Regulator transcription factors and kinases that promote AR-
 independent cell survival.
Aim 3: Identify molecular markers of transition from AR-active to AR-independent CRPC subsets and identify
 and target critical pathways that promote survival of specific AR-independent subsets.
The completion of the proposed work will lead to the development of rational clinical trials of BETi drug
combinations to block critical networks that sustain the survival of AR-independent, lethal prostate cancers.

## Key facts

- **NIH application ID:** 10247716
- **Project number:** 5P50CA097186-19
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Colm M Morrissey
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $110,615
- **Award type:** 5
- **Project period:** 2002-09-19 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247716

## Citation

> US National Institutes of Health, RePORTER application 10247716, Project 2: Targeting Emergent Vulnerabilities in AR-Inactive Prostate Cancer (5P50CA097186-19). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247716. Licensed CC0.

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