# Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $288,977

## Abstract

PROJECT SUMMARY (Project 3) 
Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease for which novel 
molecular mechanism-based combination therapy strategies are needed. We identified an androgen receptor 
(AR)- and c-Myb–co-regulated DNA damage response (DDR) gene signature that is highly correlated with 
castration-resistance, metastasis, and reduced overall survival in mCRPC patients. In this DDR gene signature 
homologous recombination (HR) DNA repair genes and HR modulator (HRM) genes are highly represented. 
The relatively large percentage of HR/HRM genes in the DDR gene signature underscores the importance of 
this group of genes to prostate cancer progression. Our preliminary preclinical studies demonstrated that 
enzalutamide (ENZ), a 2nd-generation anti-androgen that blocks androgen from binding to the androgen 
receptor (AR), suppressed the expression of a majority of the HR/HRM genes and synergized with olaparib 
(OLA), a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor in suppressing prostate cancer growth. Previously, 
OLA has been associated with synthetic lethality in multiple malignancies with BRCA1/2 or other HR gene 
deficiencies and its target, PARP1, plays a crucial role in base excision repair (BER) and was reported to 
function as an AR co-factor. In this project, we propose to test the hypothesis that targeting AR (ENZ) and 
PARP (OLA) in a “lead-in” strategy will generate synthetic lethality in mCRPC through ENZ-mediated 
downregulation of HR/HRM gene activity and OLA-mediated suppression of PARP’s enzymatic activity 
in BER and PARP’s cofactor role of AR transcriptional activity. The lead-in trial design will allow us to 
efficiently determine the clinical relevance of our biological findings by linking baseline to sequential 
modulation of target genes in individual cancers. We will test this hypothesis in three specific aims. 
Aim 1. Characterize the HR/HRM gene signature in bone marrow biopsies of men with mCRPC treated with 
 enzalutamide and/or abiraterone, novel inhibitors of androgen signaling. 
Aim 2. Further characterize the synergistic potential of and identify predictive biomarkers of response to 
 combination therapies that co-target AR (ENZ) and PARP function (OLA) using preclinical models. 
Aim 3. Conduct a clinical trial of treating CRPC patients with ENZ followed by the addition of the PARP 
 inhibitor OLA to achieve greater therapeutic response and to correlate an ENZ-regulated HR/HRM 
 gene signature to the therapeutic responses.

## Key facts

- **NIH application ID:** 10005152
- **Project number:** 5P50CA140388-10
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Timothy Charles Thompson
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $288,977
- **Award type:** 5
- **Project period:** 2009-09-02 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005152

## Citation

> US National Institutes of Health, RePORTER application 10005152, Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC (5P50CA140388-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10005152. Licensed CC0.

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