# Overcoming treatment-resistant gynecological cancers by combination of DNA damage response inhibitors

> **NIH NIH R50** · UNIVERSITY OF PENNSYLVANIA · 2024 · $112,052

## Abstract

Project Summary
 About 50% of high grade serous ovarian cancers (HGSOC) exhibit defects in homologous recombination (HR;
e.g. BRCA1/2 mutations). Approximately 20% HGSOC and 50% of serous endometrial cancer (EMCA) exhibit
CCNE1 amplification. About 50% clear cell ovarian cancer (CCOC) have ARID1A loss. My research goal is to
exploit genetic vulnerabilities in gynecological cancers with scientifically rational drug combinations.
 First, CCNE1 amplification promotes loss of G1-S checkpoint and increased reliance on the G2-M checkpoint
for survival. Ovarian and endometrial cancers with CCNE1 amplification are platinum resistant with poor
outcomes. I will test new therapies that exploit survival pathways critical for survival in CCNE1 oncogene addicted
cells. I will also determine if other biomarkers in addition to CCNE1 correlate with response to effective targeted
therapies.
 Second, rare gynecological cancers lack preclinical models for drug discovery. We will expand our existing
PDX and organoid platform to include rare tumor types. We will also test new strategies that exploit the genetics
of these rate tumor types such as low-grade serous ovarian cancer. In addition, I will perform deep genomic and
transcriptomic studies to identify biomarker signatures that predict response to DNA Damage Response (DDR)
inhibitor combinations using PDXs and patient samples from an ongoing phase IB clinical trial. I will also identify
new targets for ARID1Amut clear cell ovarian cancer using a CRISPR screen targeting functional protein domains.
 Lastly, PARP inhibitors (PARPi) represent a significant advance in ovarian cancer treatment with HR deficiency;
however, tumors ultimately acquire resistance. I showed that combination PARPi-ATRi overcomes PARPi
resistance in cell lines and PDX models (Nature Commun, 2020) which led to Phase II clinical trial. We will now
determine if combination therapy can be augmented by activating the immune system. We will test new strategies
such as radionucleotides to overcoming PARPi resistance. Lastly, we will further evaluate a non-invasive
molecular imaging tool to predict response to PARPi therapies.
 In summary, these studies have a significant impact to advance cancer therapies for women with
gynecological malignancies into the clinic.

## Key facts

- **NIH application ID:** 10978356
- **Project number:** 1R50CA283807-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Haineng Xu
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $112,052
- **Award type:** 1
- **Project period:** 2024-09-12 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978356

## Citation

> US National Institutes of Health, RePORTER application 10978356, Overcoming treatment-resistant gynecological cancers by combination of DNA damage response inhibitors (1R50CA283807-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10978356. Licensed CC0.

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