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Elucidating mechanisms of PARP inhibitor resistance in IDH-mutant cancers

Award Number: F30CA291077
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Elucidating mechanisms of PARP inhibitor resistance in IDH-mutant cancers - Isocitrate dehydrogenase (IDH) mutations are found in many malignancies including gliomas, cholangiocarcinomas, and acute myeloid leukemia. Mutations in the IDH gene lead to the neomorphic production of 2-hydroxyglurate (2HG), a competitive inhibitor of -ketoglutarate. A series of clinical studies showed enhanced sensitivity to chemotherapy and radiation therapy, and further characterization by several groups revealed DNA repair defects in IDH-mutant cancers. Our lab discovered this defect arises from 2HG-mediated inhibition of the -ketoglutarate dependent dioxygenase KDM4B, which leads to aberrant H3K9 trimethylation at the site of DNA damage, resulting in chromatin condensation and impairing recruitment of homology-directed repair proteins to the site of damage. This DNA repair defect yields IDH-mutant cancers sensitive not only to chemotherapy and radiation therapy, but also to poly (ADP-ribose) polymerase (PARP) inhibitors. This defect is currently being evaluated in clinical trials using PARP inhibitor monotherapy or in combination with other agents. Nonetheless, some patients do not respond to treatment, suggesting resistance to PARP inhibitors. Thus, a critical opportunity to uncover and to describe mechanisms of PARP inhibitor resistance in IDH-mutant cancers will be addressed here. Several studies have described mechanisms of PARP inhibitor resistance in patients with mutations in the breast cancer genes 1/2 (BRCA1/2). These studies have employed the use of PARP inhibitor resistant clonal lines, as well as a genome scale CRISPR-Cas9 knockout (GeCKO) screen and have identified restoration of homology directed repair and replication fork stabilization as mechanisms of resistance. This study will employ similar techniques to study PARP inhibitor resistance in IDH-mutant cancers. Aim 1 will determine mechanisms of PARP inhibitor resistance in IDH-mutant cancers using clonal cell lines previously established by our group. RNA sequencing data from these PARP inhibitor resistant clones exhibit differences in transcriptomic profiles, specifically downregulation of 53BP1, RIF1, and the HP1 isoforms. To deconvolute the RNA sequencing data, generating constitutive CRISPR-Cas9 knockout cell lines of these genes of interest will allow us to test sensitivity to PARP inhibition and to evaluate the effects in homology directed repair and chromatin remodeling. Aim 2, on the other hand, will identify novel genes conferring PARP inhibitor resistance in IDH1-mutant cells using an unbiased GeCKO screen. Specifically, a publicly available human GeCKO lentiviral pooled library will be transduced into IDH1-mutant cells, and further challenged with a PARP inhibitor. Two genes involved in DNA repair and two genes involved in chromatin remodeling will be selected to create constitutive CRISPR-Cas9 knockout cell lines and characterization will be conducted as in Aim 1. Together, this work will reveal undescribed mechanisms of PARP inhibitor resistance in IDH-mutant cancers, and it will provide insight into combinatorial therapy with other DNA damaging agents that may synergize to overcome this resistance.


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: 2026 ( Subtotal = $54,538 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	2	3/23/2026	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2025 ( Subtotal = $34,522 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	3/10/2025	NEW	$33,958
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	002	1	5/22/2025	NEW	$564
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	001	1	3/10/2025	NEW	$0
														Subtotal = $34,522

Grand Total All Awards = $89,060

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Elucidating mechanisms of PARP inhibitor resistance in IDH-mutant cancers

Award Number: F30CA291077

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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