# Targeting the DNA damage response with PARP and ATR inhibition to potentiate cytotoxicity and improve efficacy of immune checkpoint blockade in IDH mutant gliomas

> **NIH NIH K08** · YALE UNIVERSITY · 2021 · $231,253

## Abstract

PROJECT SUMMARY/ABSTRACT
Candidate. Dr. Vasquez is an Assistant Professor of Pediatrics at the Yale School of Medicine and a member
of the Yale Cancer Center Cancer Immunology Program and trainee in the Yale Immuno-Oncology Training
Program. This proposal is focused on the link between DNA damage and tumor immunogenicity and will
provide Dr. Vasquez with essential research skills, such as methods for interrogating DNA repair and immune
pathways and pre-clinical studies with syngeneic mouse models. Dr. Vasquez will take advanced coursework
in cancer immunology, cellular and molecular biology of cancer, computational biology, and early phase clinical
trial design. He will also participate in local and national cancer biology and immunology conferences. Dr.
Vasquez’s primary mentor, Dr. Ranjit Bindra, is a physician-scientist with an R01-funded research laboratory
and an expert in leveraging DNA repair pathways in the treatment of cancer. Dr. Vasquez’s advisory committee
includes Dr. Hideho Okada, a physician-scientist and expert in preclinical glioma immunotherapy research, Dr.
Gary Kupfer, a physician-scientist with expertise in the study of genomic instability in cancer and Dr. David
Hafler, a physician-scientist and pioneer in neuro-immunology. This multidisciplinary mentorship team, along
with the outstanding scientific resources available at Yale, will allow Dr. Vasquez to acquire additional
mentored research experience so that he may become an independently funded investigator.
Research Project. Immune checkpoint inhibitors (ICi) have, thus far, been ineffective in the treatment of
glioma, largely due to the immunologically “cold” microenvironment and the low number of neoantigens. Our
group recently discovered that IDH1/2 mutations, which are common in gliomas, induce homologous
recombination (HR) defects and confer sensitivity to DNA damage response inhibitors (DDRi), such as poly
(ADP-ribose) polymerase (PARP) inhibitors and Ataxia telangiectasia and Rad3-related (ATR) kinase
inhibitors. Emerging evidence shows that inherited or acquired DDR defects increase tumor immunogenicity
through DNA damage-induced activation of immune recognition pathways. Therefore, the central hypothesize
of my proposal is that mutant IDH1/2-induced DNA repair defects can be exploited with PARP and ATR kinase
inhibition to induce host and cancer cell-intrinsic immune activation and improve ICi response in otherwise
poorly immunogenic gliomas. In Aim 1, we will perform a series of in vitro and in vivo studies to test the
potential efficacy of combined PARP and ATR inhibition against IDH1/2-mutant glioma and explore DNA repair
mechanisms contributing to this synthetic lethality. In Aim 2, we will probe the immune-mediated mechanisms
of DDRi synthetic lethality and define the tumor-intrinsic and host-dependent immunomodulatory effects of
combined PARP and ATR inhibition. In Aim 3, we will determine whether PARP and ATR inhibition, alone or in
combination, improves t...

## Key facts

- **NIH application ID:** 10190545
- **Project number:** 1K08CA258796-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JUAN C VASQUEZ
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $231,253
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190545

## Citation

> US National Institutes of Health, RePORTER application 10190545, Targeting the DNA damage response with PARP and ATR inhibition to potentiate cytotoxicity and improve efficacy of immune checkpoint blockade in IDH mutant gliomas (1K08CA258796-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10190545. Licensed CC0.

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