# Project 1: Resistance caused by AR pathway reactivation

> **NIH NIH U54** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $330,155

## Abstract

Project 1 Summary/Abstract 
Project 1 of the MSKCC-UW/Fred Hutch Prostate Cancer Drug Resistance and Sensitivity Center focuses on 
acquired resistance to hormone therapy that is caused by androgen receptor (AR) pathway reactivation. The 
project consists of two Aims, based on two different mechanisms of AR pathway activation. Aim 1 focuses on 
the glucocorticoid receptor, which we and others have shown can substitute for AR to drive tumor growth 
through a bypass mechanism. Clinical datasets, albeit limited at this stage, suggest that this mechanism could 
be responsible for 20-30% of acquired resistance to enzalutamide. The experiments in Aim 1 will explore the 
preclinical activity of treatment regimens that target AR in combination with a competitive antagonist of GR 
(from ORIC Pharmaceuticals) or with a BET domain inhibitor (from Constellation Pharmaceuticals) that 
potently downregulates GR expression. Aim 2 addresses the more common circumstance where alteration of 
AR itself is responsible for AR pathway reactivation, a circumstance present in more than 50% of acquired 
resistance patients. This can occur through AR gene amplification, AR mRNA splice variants or AR mutations, 
roughly in that order of frequency. Experiments in Aim 2 are designed to inhibit AR more potently than is 
currently possible with current antagonists such as enzalutamide, first by interfering with the transcription of AR 
and its downstream target genes using a CBP/p300 inhibitor (from AbbVie). We will also evaluate a tool 
compound targeting the chromatin modifier G9A/EHMT2 that we recovered in a whole genome shRNA screen, 
based on selective antiproliferative activity in combination with enzalutamide. Finally, we will conduct a screen 
for drug targets that further impair AR transcriptional output beyond that seen with enzalutamide. In total, we 
will evaluate four AR combination therapy regimens, three of which involve drugs that are currently in clinical 
development or soon will be. In summary, this Project has the potential to generate multiple mechanism-based 
combination therapy clinical trials together with insights into how to select patients using clinically feasible 
biomarkers. Furthermore, the findings could be more broadly relevant to other hormone receptor dependent 
diseases such as breast cancer.

## Key facts

- **NIH application ID:** 10250361
- **Project number:** 5U54CA224079-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** CHARLES L. SAWYERS
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,155
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250361

## Citation

> US National Institutes of Health, RePORTER application 10250361, Project 1: Resistance caused by AR pathway reactivation (5U54CA224079-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10250361. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*