# Targeting and DNA damage response in breast cancer

> **NIH NIH P50** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $325,339

## Abstract

PROJECT SUMMARY/ABSTRACT: TARGETING DNA DAMAGE RESPONSE IN BREAST 
CANCER 
The increased genome instability caused by DNA repair defects can be exploited using synthetic lethal 
approaches. For example, poly-ADP-ribose polymerase (PARP) inhibitors including olaparib have been 
approved to treat breast and ovarian cancer patients harboring mutations in BRCA1 or BRCA2. These drugs 
are thought to work by targeting defects in homology-directed repair (HR) of double-strand breaks (DSBs). 
However, HR proteins, including BRCA1 and BRCA2, “moonlight” to regulate replication fork stability, and 
there is increasing evidence that these replication fork functions can be important determinants of PARP 
inhibitor outcomes independently of HR. Importantly, PARP inhibitor resistance is an increasing clinical 
problem. Thus, defining clinically relevant resistance mechanisms, biomarkers of resistance, and ways to 
overcome or prevent resistance are important research goals. This proposal addresses these issues both at 
the mechanistic and patient levels. Our overall goal is to improve patient outcomes by defining the 
mechanisms by which HR proteins regulate replication fork stability, understanding the contribution of 
replication fork dynamics to PARP inhibitor sensitivity, and identifying drug combinations that can be used to 
overcome resistance. We will use cell culture and patient-derived xenograft models to define mechanisms that 
influence PARP inhibitor sensitivity, utilize patient-derived 3D-ex vivo organoid cultures to examine 
mechanisms of PARP inhibitor resistance and explore rational drug combinations that can overcome 
resistance mechanisms in clinical trials. Completing these studies will test the hypothesis that fork protection is 
an important determinant of therapeutic efficacy of PARP inhibitors, identify therapeutic strategies to overcome 
resistance and potentially provide a rationale for expansion of PARP inhibitor use for clinical investigation and 
treatment.

## Key facts

- **NIH application ID:** 10456743
- **Project number:** 5P50CA098131-20
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** David K Cortez
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $325,339
- **Award type:** 5
- **Project period:** 2003-08-07 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456743

## Citation

> US National Institutes of Health, RePORTER application 10456743, Targeting and DNA damage response in breast cancer (5P50CA098131-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10456743. Licensed CC0.

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