# Project 3 - Improving Therapy for DNA-Damage Deficient Pancreatic Adenocarcinoma

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2020 · $245,850

## Abstract

Project Summary
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United
States. Up to 20% of PDAC patients harbor germline or somatic mutations in genes involved in double-strand
DNA damage repair (DDR), including the homologous recombination (HR) repair pathway genes BRCA1,
BRCA2 and PALB2, as well as genes involved in the DNA damage response, such as ATM and CHEK2. A
subset of PDAC patients with mutations in BRCA1 and BRCA2, as well as other DDR genes, may have durable
tumor responses to poly(ADP-ribose) polymerase (PARP) inhibitors; however, the optimal biomarkers have not
been identified to predict which patients will benefit from these therapies. Furthermore, combination treatment
programs to move beyond single-agent PARP inhibition are not yet defined. This proposal brings together a
team of distinguished laboratory, translational and clinical investigators to: (1) define optimal genomic and
functional strategies for identifying PDAC patients with DDR deficiency; (2) conduct treatment trials to identify
the patients with greatest benefit from PARP inhibition and to identify mechanisms of de novo and acquired
resistance; and (3) to define novel combination treatment strategies for future clinical trials. In Aim 1 of this
proposal, we will define scalable genomic and functional assays, including novel mutational signatures, a novel
DNA replication fork stability assay, and immunohistochemical assays for RAD51 foci, that identify patients with
PDAC harboring HR deficiency (HRD) or other DDR defects, so that clinicians can efficiently select PDAC
patients most likely to benefit from targeted therapies. In Aim 2, we will perform an investigator-initiated, phase
2 clinical trial to determine the efficacy of the PARP inhibitor niraparib in DDR-mutant PDAC and will identify
determinants of sensitivity and mechanisms of acquired resistance. In Aim 3, we will identify combination
treatment strategies for patients with DDR-deficient PDAC using novel patient-derived organoid lines that model
PARP inhibitor sensitivity and resistance in both DDR deficient and proficient contexts. Leveraging unique
genomic analyses, innovative DDR deficiency assays, novel patient-derived models, a large clinical volume of
PDAC patients, a multi-disciplinary team-science approach, and close collaboration with the Biospecimens and
Pathology Core (Core B) and the Biostatistics and Bioinformatics Core (Core C), this proposal will deliver (1)
clear biomarker strategies by which clinicians can identify patients with DDR-deficient PDAC, (2) data for the
responsiveness of DDR-deficient PDAC to PARP inhibition, (3) new mechanistic insights into resistance
mechanisms to PARP inhibition in PDAC, and (4) combination strategies for testing in the next generation of
PDAC clinical trials. Through these studies, we aim to make meaningful improvements in treatment strategies
for this important subset of PDAC patients who harbor DDR deficie...

## Key facts

- **NIH application ID:** 10005199
- **Project number:** 5P50CA127003-12
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Brian Matthew Wolpin
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,850
- **Award type:** 5
- **Project period:** 2007-04-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005199

## Citation

> US National Institutes of Health, RePORTER application 10005199, Project 3 - Improving Therapy for DNA-Damage Deficient Pancreatic Adenocarcinoma (5P50CA127003-12). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10005199. Licensed CC0.

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