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Molecular Dynamics of Glioma Formation and DNA Damage Response by Mutant IDH1

Award Number: K08CA283279
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/06/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Molecular Dynamics of Glioma Formation and DNA Damage Response by Mutant IDH1 - Project Summary/Abstract: Gliomas are the most common primary brain tumors in adults, a subset of which have mutations in the metabolic gene isocitrate dehydrogenase 1 (IDH1). Cancer-associated IDH1 mutants (the most common of which is IDH1R132H) are neomorphs that produce the oncometabolite 2-hydroxyglutarate [(R)-2HG], which is thought to contribute to glioma formation. Mutant IDH (mIDH) inhibitors that block (R)-2HG production have been recently shown to improve outcomes in lower-grade IDH-mutant glioma patients and are poised to become standard-of- care. However, response to mIDH inhibitors is heterogeneous, and our understanding of how these drugs may work in glioma has been severely limited by a lack of faithful animal models of lower-grade IDH-mutant gliomas. In an effort to better understand these unanswered questions regarding mIDH1 biology, I made a genetically engineered mouse (GEM) model of mIDH1-driven grade 3 astrocytoma that circumvents key limitations of existing models and provides the opportunity to address fundamental unanswered questions regarding mIDH biology in lower-grade gliomas. I leveraged this GEM and other models to show that IDH-mutant gliomas are sensitive to de novo pyrimidine synthesis inhibitors (e.g. dihydroorotate dehydrogenase (DHODH) inhibitors) due to an increased susceptibility of IDH-mutant cells to DNA damage caused by these drugs. However, whether this sensitivity to DNA damage extends to other standard-of-care therapies, and the mechanisms underlying these effects, is not fully understood. My overall objective is to leverage the key advantages of my grade 3 IDH-mutant GEM to address fundamental questions regarding mutant IDH in glioma: I will determine the response of my GEM model to mIDH inhibitors and evaluate molecular signatures of mIDH inhibitor treatment, determine whether mIDH inhibitors and/or DHODH inhibitors alter response to radiation, and identify mechanisms underlying how IDH-mutant gliomas respond to DNA damaging treatments. I am a radiation oncologist with a research background in glioma biology and a long-term goal of directing my own independent laboratory as an academic physician scientist. I aim to focus my research on understanding the mechanisms driving glioma growth, with the goal of harnessing this knowledge to develop novel therapeutic strategies. I am conducting research in the laboratory of Dr. William G. Kaelin, Jr., MD at Dana-Farber Cancer Institute (DFCI), which I will continue during my proposed K08 research. As an Instructor, 80% of my time is spent on research in the Kaelin lab and 20% is on patient care treating patients with glioma tumors. I have assembled an expert Scientific Advisory Committee to help guide my research and career development: (1) Dr. Stephen Elledge, PhD (Harvard Medical School), (2) Dr. Alan D’Andrea, MD, (DFCI), (3) Dr. Bradley Bernstein, MD/PhD (DFCI), and (4) Dr. Samuel McBrayer, PhD (UT Southwestern). My clinical mentors are Dr. Patrick Wen and Dr. Daphne Haas-Kogan, both world leaders in neuro-oncology. My training in this environment will be outstanding preparation to achieve my long-term career goals as an independent investigator.


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 = -$216,642 )
2026	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	2	3/24/2026	NON-COMPETING CONTINUATION	$0
2026	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	001	2	3/27/2026	NON-COMPETING CONTINUATION	-$216,642
														Subtotal = -$216,642

Issue Date FY: 2025 ( Subtotal = $299,403 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	2	3/13/2025	NON-COMPETING CONTINUATION	$299,403
														Subtotal = $299,403

Issue Date FY: 2024 ( Subtotal = $299,403 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	1	5/6/2024	NEW	$299,403
														Subtotal = $299,403

Grand Total All Awards = $382,164

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Molecular Dynamics of Glioma Formation and DNA Damage Response by Mutant IDH1

Award Number: K08CA283279

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/06/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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