# Mechanisms of radioresistance and strategies for radiosensitization in ovarian clear cell carcinoma

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $166,743

## Abstract

DESCRIPTION
Ovarian clear-cell carcinoma (OCCC) is the second most common type of ovarian cancer and is associated
with poor survival because of the lack of effective therapeutic options. Our long-term goal is to understand the
molecular mechanisms that create therapeutic opportunities in OCCC and to translate such discoveries into
meaningful clinical applications.
ARID1A, a component of the chromatin remodeling complex SWI/SNF, is mutated in more than 50% of OCCC.
With the support of our current R01 project, we have established a successful research program to study the
role of the ARID1A-SWI/SNF complex in regulating the DNA damage response (DDR) and DNA repair. In the
preliminary studies leading to this renewal application, we discovered a new role for the ARID1A-SWI/SNF
complex in transcriptional silencing of heterochromatin repetitive DNA sequences, namely satellite DNA
element (satDNA) in response to ionizing radiation (IR)-induced DNA damage. We also showed that aberrant
IR-induced satRNA expression activates RNA-sensing innate immune response in ARID1A-deficient cells.
These exciting and promising findings have led us to hypothesize that ARID1A deficiency unleashes IR-
induced de-repression of heterochromatin repetitive satDNA sequences by impairing DNMT3A-mediated DNA
methylation and transcriptional silencing. This consequently activates the dsRNA-sensing RIG-1/MDA5
pathway, and provides the rationale to use ATM inhibitors to enhance the efficacy of radiotherapy and
immunotherapy by selectively modulating nucleic acid-mediated innate immune response in ARID1A-deficient
tumors. We will employ multidisciplinary approaches, including molecular/biochemistry/cell biology-based
mechanistic studies, shRNA/CRISPR-Cas9-based genetic studies, bioinformatic analysis and preclinical
animal model-based translational studies, and analysis of OCCC patient samples to test this hypothesis.
Together, our proposed project will not only mechanistically advance our fundamental understanding of the
underlying biology of how the ARID1A-SWI/SNF chromatin remodeling complex maintains heterochromatin
transcriptional silencing to radiation-induced DNA damage, but will also develop new personalized immune-
based radiotherapy regimens tailored to the genetic contexts of tumors, such as ARID1A deficiency or more
broadly SWI/SNF-mutated cancers.

## Key facts

- **NIH application ID:** 10926863
- **Project number:** 5R01CA181663-09
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Guang Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $166,743
- **Award type:** 5
- **Project period:** 2016-08-16 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10926863

## Citation

> US National Institutes of Health, RePORTER application 10926863, Mechanisms of radioresistance and strategies for radiosensitization in ovarian clear cell carcinoma (5R01CA181663-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10926863. Licensed CC0.

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