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Isocitrate dehydrogenase (IDH) mutations as drivers of organelle stress and dysfunction

Award Number: R35GM137773
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Isocitrate dehydrogenase (IDH) mutations as drivers of organelle stress and dysfunction - ABSTRACT/SUMMARY Human isocitrate dehydrogenase 1 and 2 (IDH1, IDH2), which are highly conserved across many species, are responsible for the reversible NADP+-dependent oxidation of isocitrate (ICT) to α-ketoglutarate (αKG). Mutations in IDH have been implicated in > 80% of lower grade gliomas, 40% of chondrosarcomas, and ≤ 20% of acute myeloid leukemia cases. Though their conventional activity typically is ablated, IDH1 and IDH2 mutations confer a neomorphic activity: the NADPH-dependent production of oncometabolite D-2- hydroxyglutarate (D2HG). D2HG inhibits αKG-dependent enzymes like DNA and histone demethylases leading to epigenetic changes, and NADPH depletion can result in oxidative stress. The most common point mutations found in tumors are IDH1 R132H and IDH2 R140Q and R172K, though many other amino acid substitutions have been reported at these positions. Though much progress has been made in understanding the role of IDH in cancer, including the development of FDA-approved inhibitors, many key fundamental questions remain. We have recently shown that mutations in IDH1 have unique catalytic profiles, and we used a host of structural methods to elucidate mechanisms driving these kinetic differences. This work highlighted a surprising gap in our understanding of IDH – it is not yet clear which residues drive the chemistry of the neomorphic reaction. Here, we seek to determine the key features of disease-driving IDH1 and IDH2 mutants, including elucidating the interactions of wild type and mutant monomers upon dimerization to form the catalytic dimer, and the mechanisms of substrate binding and catalysis. A comprehensive understanding of kinetic and structural features of IDH1 and IDH2 mutants is important for elucidating the mechanistic features of dehydrogenases, a ubiquitous enzyme class. These discoveries can also serve to guide development of next generation inhibitors, and to help predict patient response to therapies. We also recently showed that unique IDH1 catalytic profiles can in turn alter D2HG levels in vitro and in vivo to affect tumor aggressiveness. Here, we return our focus to the most common mutations found in patients as we seek to determine the cellular consequences of IDH1 mutations beyond their role in altering DNA and histone methylation. Further, as IDH1 localizes to the cytosol and peroxisomes, this raises the possibility of organelle-specific effects of IDH1 mutations, which is an area that is underexplored. Identifying new pathways affected by IDH1 mutation allows us to better understand the roles wild type IDH1 plays to maintain healthy metabolism, as well as helps us to identify new pathways that may be ripe for therapeutic targeting. In our quest to establish the mechanisms of metabolic enzyme function in health and disease from the chemical to the in vivo levels by leveraging kinetic, structural, cellular, xenograft, and -omics technologies, we can establish the unique consequences of disease- relevant mutational variants in the most commonly mutated metabolic enzyme found in tumors.


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: 2025 ( Subtotal = $395,448 )
2025	2025	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	6	6/9/2025	COMPETING CONTINUATION	$395,448
2025	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	5/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $395,448

Issue Date FY: 2024 ( Subtotal = $376,250 )
2024	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	6/21/2024	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2023 ( Subtotal = $376,250 )
2023	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	6/21/2023	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2022 ( Subtotal = $376,250 )
2022	2022	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	6/27/2022	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2021 ( Subtotal = $453,658 )
2021	2021	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	7/14/2021	SUPPLEMENT FOR EXPANSION	$77,410
2021	2021	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	6/18/2021	NON-COMPETING CONTINUATION	$376,248
														Subtotal = $453,658

Issue Date FY: 2020 ( Subtotal = $376,248 )
2020	2020	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	8/1/2020	NEW	$376,248
														Subtotal = $376,248

Grand Total All Awards = $2,354,104

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Isocitrate dehydrogenase (IDH) mutations as drivers of organelle stress and dysfunction

Award Number: R35GM137773

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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