Saturday, February 7, 2026 2/7/2026

Targeting isocitrate dehydrogenase mutations by enzyme hyperactivation

Award Number: R01CA290231
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

Group Awards By:

View Award Description

Targeting isocitrate dehydrogenase mutations by enzyme hyperactivation - PROJECT SUMMARY/ABSTRACT Mutations in isocitrate dehydrogenase (IDH) enzymes are hallmarks of a variety of deadly cancers, including acute myeloid leukemia (AML), glioma, cholangiocarcinoma, chondrosarcoma, and T cell lymphoma. Mutant IDH enzymes drive cancer through an unusual mechanism – they produce a metabolite called 2- hydroxyglutarate (2HG) that poisons gene expression machinery and locks malignant cells in a stem cell-like state. Drugs that inhibit mutant IDH enzymes induce durable clinical responses in some patients with IDH- mutant cancers, leading to FDA approvals for AML and cholangiocarcinoma. However, despite near universal inhibition of 2HG production, over half of patients do not respond to IDH inhibitors. Even for patients who initially respond to IDH inhibitors, most eventually acquire resistance to the drugs. While the mechanisms of resistance to IDH inhibitors remain incompletely understood, emerging evidence suggests that acquisition of specific co-occurring mutations during tumor evolution results in a loss of dependence on 2HG. Therefore, we need new treatment approaches that target IDH mutations in different ways beyond simple inhibition of the enzyme. We previously identified an unusual pattern of resistance mutations in the dimer interface of mitochondrial IDH2 wherein they occur in trans (on the other allele) relative to the 2HG-producing active-site mutation. Here, we show that in contrast to the in trans mutations that drive drug resistance, forced expression of a dimer-interface mutation in cis with the active-site mutation resulted in mitochondrial dysfunction and impaired growth of leukemia cells. Biochemical and structural studies demonstrated that the in cis dimer- interface mutation enabled IDH2 to aberrantly use NADH as an additional cofactor and dramatically enhanced production of 2HG. Seeking to exploit the toxicity exerted by the in cis dimer-interface mutation, we performed a chemical screen and identified small molecules capable of mimicking this aberrant enzymatic activity with selective toxicity towards IDH2-mutant leukemia cells. Thus, we hypothesize that hyperactivation (rather than inhibition) of mutant IDH offers an unexpected and effective new strategy to target IDH-mutant cancers. This hypothesis will be rigorously tested in three Specific Aims. Aim 1 will use enzyme assays and structural approaches to elucidate the biochemical basis for mutant IDH2 hyperactivation. Aim 2 will employ in vitro and in vivo cancer models to define the mechanisms of toxicity arising from hyperactivation of mutant IDH2. Aim 3 will utilize biochemical and functional approaches to determine if the approach of hyperactivation can applied to cytosolic IDH1 mutations. The proposed studies will reshape our understanding of the oncogenic properties of 2HG and the biochemistry of neomorphic IDH activation. More fundamentally, this work will demonstrate the feasibility of an entirely novel hyperactivation approach as a strategy to harness oncogene-mediated toxicity that could be applied to a wide range of oncogenes and cancer contexts.


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 = $427,285 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	000	3	1/14/2026	NON-COMPETING CONTINUATION	$427,285
														Subtotal = $427,285

Issue Date FY: 2025 ( Subtotal = $474,760 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	001	2	6/3/2025	NON-COMPETING CONTINUATION	$47,475
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	000	2	1/16/2025	NON-COMPETING CONTINUATION	$427,285
														Subtotal = $474,760

Issue Date FY: 2024 ( Subtotal = $474,760 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	000	1	2/1/2024	NEW	$474,760
														Subtotal = $474,760

Grand Total All Awards = $1,376,805

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting isocitrate dehydrogenase mutations by enzyme hyperactivation

Award Number: R01CA290231

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer