# Project 1: Combining PARP inhibition with radiation to sensitize HR proficient pancreatic cancers to immunotherapy

> **NIH NIH P50** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $226,873

## Abstract

PROJECT SUMMARY/ABSTRACT (PROJECT 1)
We discovered that inhibitors of the DDR (DNA damage response) enhance radiation-induced T1IFN (Type I
interferon)-mediated innate immunity and, subsequently, adaptive immunity. We have also shown that PARP
inhibitors are radiation sensitizers with unique properties in inducing lesions at radiation-induced DNA damage
sites. In this application, we investigate their combination with radiation as a strategy to induce innate immunity
and sensitize PDAC (pancreatic ductal adenocarcinoma) to immunotherapy. We confirm, in agreement with a
clinical study, that radiation alone is a weak immune stimulator. In contrast, the combination of radiation with
the PARP inhibitor olaparib strongly induces T1IFN-mediated innate immunity in PDAC resulting in sensitization
of both local and systemic tumors to immunotherapy. Taken together these data support our proposed clinical
trial combining olaparib, radiation and durvalumab in patients with LAPC (locally advanced pancreatic cancer).
The overall goal of this proposal is to preclinically develop a strategy combining PARP inhibitors with radiation
for sensitizing PDAC to ICB (immune checkpoint blockade) by promoting tumor cell DNA damage and
immunogenicity that will be translated to a clinical trial in LAPC patients. We will accomplish this in 3 specific
aims. Specific Aim 1 will elucidate novel mechanisms of innate immune modulation and their T1IFN-dependent
phenotypic consequences by PARP inhibitors with radiation in PDAC cells. Our preliminary data show, in
contrast to PARP inhibitor alone, that the PARP inhibitor olaparib synergizes with radiation to reduce survival
and induce a T1IFN innate immune response in HR (homologous recombination) proficient PDAC. Aim 1 will
define novel mechanisms of T1IFN generation and its subsequent phenotypic consequences. We anticipate
defining novel pattern recognition receptor (PRR) pathways initiated by olaparib and radiation-induced DNA
damage or replication stress that result in increased tumor innate immunity. Specific Aim 2 will determine the
therapeutic benefit and molecular endpoints of combined therapy with PARP inhibitor, radiation and ICB in
PDAC. We will define the local and systemic anti-tumor efficacy and toxicity of high or lower dose per fraction
radiation (i.e., SBRT, stereotactic body radiation or standard fractioned radiation) and the optimal schedule with
olaparib and anti-PD-L1. We will establish endpoints in tumors and blood reflecting DNA damage, tumor innate
and adaptive immunity, as well as the broader immune profile (CyTOF). We expect to achieve a favorable
therapeutic index with SBRT that is associated with tumor DNA damage and T1IFN-mediated innate and
adaptive immunity. In Specific Aim 3, we will conduct a clinical trial of olaparib, radiation, and durvalumab in
patients with LAPC. We will dose escalate olaparib using the Time-to-Event Continual Reassessment Method
(TiTE-CRM) with the combination of SBRT (unless o...

## Key facts

- **NIH application ID:** 10917024
- **Project number:** 5P50CA269022-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Meredith A Morgan
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $226,873
- **Award type:** 5
- **Project period:** 2023-08-14 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917024

## Citation

> US National Institutes of Health, RePORTER application 10917024, Project 1: Combining PARP inhibition with radiation to sensitize HR proficient pancreatic cancers to immunotherapy (5P50CA269022-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10917024. Licensed CC0.

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