# DNA repair alterations in metastatic prostate cancer: functional and therapeutic implications

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $529,020

## Abstract

PROJECT SUMMARY / ABSTRACT:
Metastatic castration-resistant prostate cancer (mCRPC) is, at present, almost invariably fatal. There is
an urgent need to tailor mCRPC therapy to vulnerabilities present within individual tumors. Crosstalk
between DNA damage response and androgen receptor (AR) signaling represents one of the most
promising opportunities for personalizing prostate cancer therapy. In this application, we will investigate
the mechanistic and therapeutic implications of alterations in the three most commonly altered DNA
repair genes in mCRPC: BRCA2, BRCA1, and ATM. Using novel in vitro and in vivo models of
homologous recombination (HR) deficiency, we will interrogate the impact of BRCA2 vs. BRCA1 vs.
ATM alterations, two copy vs. one copy aberrations, and truncating vs. non-truncating mutations on
homologous recombination, androgen receptor (AR) signaling, and response to PARP inhibitors or AR-
directed therapies. We will then validate these findings in unique cohorts of mCRPC patients treated
with these agents. Finally, we will use CRISPR-based functional genomic approaches to identify novel
genetic vulnerabilities in mCPRC models that can inform the next generation of therapeutic strategies
and guide the development of clinical trials. Our study will significantly advance the mCRPC field by: 1)
developing the first human preclinical models of HR deficiency, 2) functionally characterizing the most
prevalent BRCA2, BRCA1, and ATM alterations in mCRPC, 3) better defining the mechanistic
pathways that define the response of mCRPC to PARPi and AR-directed therapies, and 4) discovering
novel targets that influence these responses. Given the prevalence of BRCA2, BRCA1, and ATM
alterations in other cancers, including breast, ovarian, and pancreatic adenocarcinomas, the
mechanisms uncovered by these studies will have clinical implications far beyond the mCRPC space,
and will represent an advance towards individualizing cancer therapy based on tumor genetic
alterations.

## Key facts

- **NIH application ID:** 10240571
- **Project number:** 5R01CA230516-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Alan Ashworth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $529,020
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240571

## Citation

> US National Institutes of Health, RePORTER application 10240571, DNA repair alterations in metastatic prostate cancer: functional and therapeutic implications (5R01CA230516-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10240571. Licensed CC0.

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