# Research Project 3: Optimizing DNA damage repair-targeted combination therapy

> **NIH NIH U54** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $222,813

## Abstract

Abstract 
There is growing interest in targeting DNA damage repair (DDR), however predictive markers are largely 
lacking and optimal combinations with targeted therapies have not been elucidated. In preliminary studies, we 
have shown that poly (ADP-ribose) polymerase (PARP) inhibitors have antitumor efficacy not only in PDX 
models with germline BRCA mutations, but also in PDX models with other germline or somatic alterations in 
DDR genes. Further, we have shown that K-Ras mutant cell lines are resistant to PARP inhibitors and that 
MEK inhibitors enhance the antitumor efficacy of PARP inhibitors. In other work, we have found that there is a 
significant enrichment of PI3K pathway alterations in patients with mutations in DDR genes (p=0.008). We 
propose that clinically and molecularly annotated PDX models can help identify predictive markers of response 
to DDR inhibitors and can be used to develop rational combination therapies. Our long term goal is to use 
molecular features of each patient’s tumor to optimize therapy selection. As a PDX development and trial 
center, we expect to build a large panel of PDXs to facilitate genotype (and other molecular subtype)- 
phenotype correlation. We hypothesize that tumors with DDR defects will be more likely to benefit from DNA 
damage inhibitors (such as PARP, ATR, Wee1), and that targeting actionable genomic co-alterations and 
adaptive responses may enhance anti-tumor efficacy.

## Key facts

- **NIH application ID:** 10009289
- **Project number:** 5U54CA224065-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** FUNDA MERIC-BERNSTAM
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $222,813
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10009289

## Citation

> US National Institutes of Health, RePORTER application 10009289, Research Project 3: Optimizing DNA damage repair-targeted combination therapy (5U54CA224065-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10009289. Licensed CC0.

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