# Developing biomarkers of response for a new therapy in ovarian cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $692,527

## Abstract

PROJECT SUMMARY
 Clear cell ovarian cancer (CCOC) is one of the most challenging subtypes of ovarian cancer (OVCA) to treat,
as it is resistant to standard chemotherapy and is associated with poor outcomes. CCOCs likely arise from
endometriosis, supporting their unique molecular landscape with ARID1A-inactivating mutations (ARID1Amut)
being the most prevalent (50%). Our proposed research capitalizes on the high prevalence of ARID1Amut in
CCOC using a novel synthetic lethal approach to provide a new treatment option for patients addressing a
clinically unmet need. Our preliminary data shows that ARID1A loss sensitizes CCOC tumors to combination
ATR and BET family protein inhibition (ATRi-BETi). ATRi-BETi treatment is synergistic in killing CCOC cells and
patient-derived xenograft (PDX) tumors, compared to monotherapies in an ARID1A-dependent manner. These
results have led to a Phase IB investigator-initiated clinical trial that will be run through the NRG cooperative
clinical trials group evaluating next-generation ATRi (M1774) and BETi (ZEN-3694) in recurrent CCOC.
 The overarching goals of the research proposed herein are to develop ARID1A as a biomarker for ATRi-
BETi treatment and to identify new functionally relevant biomarkers that will facilitate patient selection for this
therapy for CCOC in future clinical trials. These goals will be realized through the use of human samples collected
from this clinical trial complemented by the use of CCOC PDX models and response data, which will be employed
to validate ARID1Amut as a predictive biomarker of response and help identify novel biomarkers that further
enhance the effectiveness of this combination. Novel predictive biomarkers will be identified using a multi-
dimensional molecular profiling approach that integrates: 1) mutations and gene expression alterations that
correlate with responsiveness in humans and animal models as determined by computational modeling; and 2)
factors that impact the response to drug treatment at the molecular site of BETi-ATRi action, the genome, and
the DNA replication fork. This approach is designed to discover mechanistically relevant biomarkers that predict
response to therapy. Our overarching hypothesis is that ARID1Amut and additional molecular alterations will serve
as biomarkers of response to ATRi-BETi in CCOC. In summary, these proposed studies will: 1) provide a new
treatment option for CCOC addressing a clinically unmet need; 2) determine if ARID1A loss is a biomarker of
response to ATRi-BETi; and 3) identify additional mechanistically relevant biomarkers of response to guide future
clinical trials.

## Key facts

- **NIH application ID:** 10779400
- **Project number:** 1R01CA285965-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Eric J Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $692,527
- **Award type:** 1
- **Project period:** 2024-02-15 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10779400

## Citation

> US National Institutes of Health, RePORTER application 10779400, Developing biomarkers of response for a new therapy in ovarian cancer (1R01CA285965-01). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/10779400. Licensed CC0.

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