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

Award Number: K08CA258796
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Targeting the DNA damage response with PARP and ATR inhibition to potentiate cytotoxicity and improve efficacy of immune checkpoint blockade in IDH mutant gliomas - 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 the response to anti-PD-1 in vivo.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2027 ( Subtotal = $0 )
2027	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	5	10/21/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $231,253 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	5	7/18/2025	NON-COMPETING CONTINUATION	$231,253
														Subtotal = $231,253

Issue Date FY: 2024 ( Subtotal = $231,253 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	4	7/9/2024	NON-COMPETING CONTINUATION	$231,253
														Subtotal = $231,253

Issue Date FY: 2023 ( Subtotal = $231,253 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	3	9/6/2023	NON-COMPETING CONTINUATION	$231,253
														Subtotal = $231,253

Issue Date FY: 2022 ( Subtotal = $231,253 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	2	8/8/2022	NON-COMPETING CONTINUATION	$231,253
														Subtotal = $231,253

Issue Date FY: 2021 ( Subtotal = $231,253 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	7/27/2021	NEW	$231,253
														Subtotal = $231,253

Grand Total All Awards = $1,156,265

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

Award Number: K08CA258796

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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