# Project 3: Investigating new treatment approaches based on DNA repair vulnerability in ARID1A mutated type I ovarian cancer

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2024 · $449,464

## Abstract

PROJECT 3: PROJECT SUMMARY
Cancer sequencing studies by our group and others have identified frequently occurring somatic mutations of a
chromatin remodeling protein, ARID1A, in Type I ovarian cancers including clear cell and endometrioid subtypes.
The mutations are mostly frameshift or non-sense types, resulting in truncated, unstable protein products.
Consequently, cancer cells with these loss-of-function ARID1A mutations (ARID1Amut) do not show detectable
ARID1A proteins and functionally lose cell cycle checkpoint control and have reduced DNA damage repair
capability.
The overall goal of this proposal is to evaluate the possibility that the functional characteristics of ARID1Amut
ovarian cancers can be exploited for developing effective treatments. Specifically, we will interrogate the
functional capacity of DNA base excision repair (BER) in ARID1Amut ovarian cancer cells and in endometrial
epithelial cells (the precursor of ovarian clear cell and endometrioid cancer) with engineered knockout of the
ARID1A gene. BER is considered a dominant repair mechanism for alkylating drug-induced or oxidative stress-
induced DNA lesions, and its function is often jeopardized in aging and in cancer cells. Based on higher
abundance of accumulated DNA base lesions and unresolved AP sites in ARID1A-KO vs –WT cells, we
hypothesize that loss-of-function ARID1Amut in cancer cells causes compromised base lesion DNA repair. A
BER defect in ARID1Amut Type I ovarian cancer would explain the selective sensitivity to PARP inhibitors, which
trigger replication stress response, replication fork arrest, and lethal DNA break formation as a result of excessive
PARP trapping. These characteristics in Type I ovarian cancer cells provide opportunities for highly specific
therapeutic approaches with significant potential for reduced toxicity to normal tissues and organs. The findings
will be pivotal for evaluating whether an oral alkylating drug, temozolomide, in combination with PARP inhibitors
represents an effective approach for treating ovarian clear cell carcinomas, which are often intrinsically resistant
to chemotherapy.
We will collaborate with Impact Therapeutics, Inc. to use the PARP inhibitor, senaparib (IMP4297), whose safety
and tolerability in combination with temozolomide has been reported in an ongoing Phase Ib/II trial for solid
tumors (NCT04434482). In the current study, we propose a Phase II clinical trial to evaluate efficacy of the
combination of TMZ and senaparib in treating patients with Type I ovarian cancers. The loss-of-function
ARID1Amut in Type I ovarian cancer cells provides an opportunity for a highly specific therapeutic approach with
significant potential of reduced toxicity.
The proposed studies are considered to be high impact because a comprehensive understanding of how
ARID1A-deficiency influences the cancer cell replication stress response and resultant effects on DNA replication
and damage repair may facilitate the development of new therap...

## Key facts

- **NIH application ID:** 10935408
- **Project number:** 2P50CA228991-06A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Stephanie Gaillard
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $449,464
- **Award type:** 2
- **Project period:** 2018-09-18 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935408

## Citation

> US National Institutes of Health, RePORTER application 10935408, Project 3: Investigating new treatment approaches based on DNA repair vulnerability in ARID1A mutated type I ovarian cancer (2P50CA228991-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10935408. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*