# Targeting base damage repair in BRCA-mutant cancers

> **NIH NIH R37** · WASHINGTON UNIVERSITY · 2024 · $393,943

## Abstract

PROJECT SUMMARY/ABSTRACT
Poly (ADP-ribose) polymerase inhibitors (PARPi) are a mainstay for the chemotherapeutic regimen of BRCA
mutant ovarian and breast cancers. Despite initial positive responses, long -term clinical success with PARPi
therapy is limited owing to the inevitable emergence of resistance and the side effects associated with the
current dosage. We and others recently reported that loss of a nucleosome sliding enzyme, Amplified in
Liver Cancer 1, (ALC1), hypersensitizes BRCA mutant cancer cells to PARPi. Notably, ALC1 loss permits
killing of BRCA mutant cancer cells at sub-nanomolar PARPi dosage and restores PARPi sensitivity across
various engineered models of chemoresistance. Based on these observations, our overarching goal is to
employ ALC1-deficient BRCA mutant cancer cells to define the cellular and biochemical mechanisms that
can be exploited to circumvent clinical hurdles associated with PARPi. Our preliminary data highlight a role
of ALC1 mediated nucleosome sliding in promoting the repair of base damage lesions called abasic sites.
However, it is unclear how ALC1 loss generates abasic sites and how this contributes to PARPi
hypersensitivity in BRCA mutant cancer cells. The proposal addresses this knowledge gap via the following
Specific Aims. In Specific Aim 1, we will integrate in vitro reconstitution, genetic complementation analysis
and DNA repair and replication assays to define the mechanism(s) that lead to increased abasic sites on
the chromatin upon the loss of ALC1. These experiments will provide new mechanistic insights into how
perturbing chromatin remodeling involved in base damage repair can be leveraged for augmenting PARPi
sensitivity in BRCA mutant cancers. In Aim 2, we will use single-molecule replication tract labeling assays,
electron microscopy and CRISPR-based genetic editing of patient-derived primary cells to determine how
abasic sites results in remodeling of replication forks and generation of lesions that accentuate PARPi
sensitivity. These experiments will uncover how the communication between base damage repair and
replication forks can be exploited to enhance the therapeutic potential of PARPi. Our studies will provide the
foundation to develop new approaches to improve the efficacy and toxicity profile of clinically used PARPi
while simultaneously highlighting new biomarkers that can effectively predict PARPi responses in BRCA
mutant patients.

## Key facts

- **NIH application ID:** 10979730
- **Project number:** 1R37CA286908-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Priyanka Verma
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $393,943
- **Award type:** 1
- **Project period:** 2024-07-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979730

## Citation

> US National Institutes of Health, RePORTER application 10979730, Targeting base damage repair in BRCA-mutant cancers (1R37CA286908-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979730. Licensed CC0.

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