# Research Project 4:Investigating and targeting the glucocorticoid receptor (GR) in enzalutamide- and abiraterone-resistant prostate cancer

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $177,881

## Abstract

The androgen receptor (AR)-directed agents enzalutamide and abiraterone acetate are standard first-line
therapies for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). These
agents are generally well tolerated and effective at delaying disease progression, prolonging survival, and
improving quality of life, but both drugs have limited durations of effectiveness. Patients with refractory disease
typically have poor responses to subsequent AR-targeted agents, and there is currently no predictive
biomarker that aids in the selection of a second-line therapy. Our group and others have identified upregulation
of the glucocorticoid receptor (GR) as one mechanism of resistance to enzalutamide and abiraterone acetate.
Our findings suggest that 1) GR may be a biomarker that can predict whether a patient will respond to
enzalutamide or abiraterone and 2) blocking GR upregulation in enzalutamide- and abiraterone-resistant
patients could result in tumor responses. In preliminary data, we show that isoforms of GR with variable N-termini
can be expressed in metastatic CRPC, including one called GRαC that has increased capacity to
promote enzalutamide resistance and is detectable in some patient-derived organoid cultures. It will be
necessary to characterize GRαC and other GR isoforms in order to develop GR as a biomarker and a
therapeutic target. Using a laboratory model of enzalutamide resistance, we have also found that GR
expression is epigenetically modulated, and that treatment with an inhibitor of the BET family of proteins
suppresses GR expression and restores enzalutamide sensitivity. Expanding on these findings, we will
leverage our group’s laboratory and clinical expertise to 1) investigate the role of GR isoforms in resistance to
enzalutamide, 2) define the broader effects of BET inhibition across a range of preclinical models of prostate
cancer, and 3) investigate the activity of a novel BET inhibitor in men with metastatic CRPC whose disease
has progressed on enzalutamide or abiraterone acetate.

## Key facts

- **NIH application ID:** 9998863
- **Project number:** 5P50CA092629-20
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** CHARLES L. SAWYERS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $177,881
- **Award type:** 5
- **Project period:** 2001-09-14 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998863

## Citation

> US National Institutes of Health, RePORTER application 9998863, Research Project 4:Investigating and targeting the glucocorticoid receptor (GR) in enzalutamide- and abiraterone-resistant prostate cancer (5P50CA092629-20). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998863. Licensed CC0.

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