# Mechanisms of Selective Therapeutic Synergy of PARP-inhibition and CTLA4 Blockade Engaged by Interferon-gamma in the Ovarian Tumor Microenvironment

> **NIH NIH R37** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $334,312

## Abstract

Abstract
The high mortality rate associated with ovarian cancer results from the failure of tumor-directed therapy to
produce lasting treatment responses. Durable survival in patients with other solid tumors has recently been
achieved using immune checkpoint antibodies, however similar results have not been observed in women
with ovarian cancer. Published work from our lab demonstrates that combining poly(adenosine
diphosphate-ribose) polymerase (PARP) inhibitors (PARPi) with immune checkpoint blockade can achieve
long-term survival in ovarian cancer models. The scientific premise for this study is based accumulating
evidence of a dynamic interaction between PARPi and the tumor microenvironment (TME) that regulates
treatment response and disease outcomes. Work to date has identified a tumor-intrinsic mechanism by
which PARPi interact with interferon gamma (IFNg) to promote immunogenic cell death in ovarian cancer
cells. This results in activation of tumor immunity in vivo, associated with the successful induction of
protective immune memory. Evidence that conditions in the tumor environment significantly modulate the
therapeutic efficacy of PARP-inhibitors, termed “contextual synthetic lethality”, presents an opportunity to
maximize patient outcomes and target treatment effects to the TME. Here we propose to examine the
contribution of PARP trapping by different PARPi on these tumor-intrinsic mechanisms to determine
whether we can induce similar results in BRCAwt cancers. We will additionally expand studies of tumor-
extrinsic immune modulation by PARPi in the TME to test whether macrophage polarization can engage
secondary mechanisms of CTLA4ab to enhance treatment outcomes. Finally we will validate candidate
biomarkers of response in patients enrolled in two clinical trials, and will examine associations with immune
profiling in collaboration with the Cancer Immune Monitoring Analysis Centers. With the rapid adoption of
immune checkpoint antibodies and PARP-inhibitors for the treatment of ovarian cancer and other tumor
types, this proposal has potential for immediate clinical impact through current and planned clinical trials.

## Key facts

- **NIH application ID:** 10655058
- **Project number:** 4R37CA229221-06
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Sarah Foster Adams
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $334,312
- **Award type:** 4N
- **Project period:** 2019-02-18 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10655058

## Citation

> US National Institutes of Health, RePORTER application 10655058, Mechanisms of Selective Therapeutic Synergy of PARP-inhibition and CTLA4 Blockade Engaged by Interferon-gamma in the Ovarian Tumor Microenvironment (4R37CA229221-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10655058. Licensed CC0.

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