# Sensitizing High Grade Serous Cancers to Immunotherapy through the Induction of DNA Damage

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $356,850

## Abstract

Project Summary
Immune checkpoint receptor (ICR) blockade as a cancer treatment strategy has yielded favorable response
rates in some solid tumor types, yet cellular mechanisms of immune escape have resulted in limited efficacy
in other tumors, including high grade serous carcinoma (HGSC). Our long-term goal is to understand the link
between DNA damage repair (DDR) and HGSC immunogenicity, in order to develop combinatorial
treatments for HGSC through DDR inhibition that turn hypoimmunogenic or “cold” HGSC into “hot” tumors
with improved responses to immunotherapy. The current knowledge regarding DDR in HGSC has focused on
the homologous recombination (HR) pathway. There is a fundamental gap in knowledge regarding the link
between other DDR pathways and immune response; the objective of this proposal is to bridge that gap so
that we can address the unmet need of treatment strategies for HGSC patients for whom immunotherapy or
PARP inhibitor therapy, either alone or in combination, is ineffective. Our central hypothesis is that the
inhibition of the non-homologous end joining (NHEJ) pathway is a novel immune priming strategy to
sensitize cold HGSC to immune checkpoint blockade. Through the characterization of the role of NHEJ
protein DEK in the pathogenesis of HGSC, we have identified a downstream targetable kinase, aurora kinase
A (AURKA), that serves as a novel and potent checkpoint against DNA damage and type-I interferon (IFN-I)
signaling. To test our central hypothesis, we will focus on three specific aims. Aim 1. To test the hypothesis
that the inhibition of NHEJ results in robust IFN-I signaling. Aim 2. To characterize the mechanism by which the
inhibition of NHEJ induces immune cell activation. Aim 3. To test the hypothesis that NHEJ inhibition sensitizes
cold HGSC to immune checkpoint blockade. The experiments for these aims will be carried out using human
HGSC cell lines with known BRCA mutation status and HR-proficiency or HR-deficiency as well as primary,
patient derived tumor cells established in cell culture. To characterize the immune changes following NHEJ
inhibition in tumor cells and the interplay with host immune cells, we will employ the ID8/p53-/- and ID8/p53-/-
/BRCA1-/- mouse cell lines on the C57BL/6 background to allow for studies utilizing established genetic
knockouts of critical IFN-I signaling proteins. A second, genetically engineered mouse model of HGSC will also
be studied. As outcomes of our work, we expect our findings to contribute to our understanding of the link
between NHEJ and tumor immunogenicity. Furthermore, this work will provide critical insights into treatment
strategies for HR proficient and BRCA wild-type cancers in which current PARP inhibitor-based therapies are
less effective. These contributions will be significant, as they will define the underlying mechanisms and lead to
effective combinatorial strategies for the treatment of HGSC and other solid malignancies, allowing us to move
forward with imm...

## Key facts

- **NIH application ID:** 10200717
- **Project number:** 5R01CA251198-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Karen McLean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200717

## Citation

> US National Institutes of Health, RePORTER application 10200717, Sensitizing High Grade Serous Cancers to Immunotherapy through the Induction of DNA Damage (5R01CA251198-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200717. Licensed CC0.

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