# Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)

> **NIH NIH P50** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $341,279

## Abstract

Discovery of a recurrent hotspot IDH1 mutation in the vast majority of low-grade gliomas
and secondary glioblastomas has revolutionized our understanding of the molecular pathogenesis of these
malignancies. The canonical glioma-associated IDH1 mutation encodes a mutant isocitrate dehydrogenase
enzyme, IDH1 R132H, that gains the neomorphic ability to convert 2-oxoglutarate (2-OG) to the
‘oncometabolite’ R-2-hydroxyglutarate (2-HG). Consequently, 2-HG accumulates to millimolar levels in IDH1
mutant gliomas, representing a 100- to 1000-fold increase relative to normal brain tissue. The structural
similarity between 2-HG and 2-OG enables 2-HG to competitively modulate the activity of many 2-OGdependent
dioxygenases, including JmjC family histone demethylases, TET family DNA hydroxylases, and the
hypoxia-responsive prolyl hydroxylase EglN1. Studies from our group and others demonstrate fundamental
roles for epigenetic rewiring and HIF1alpha suppression in the oncogenic program induced by IDH1 mutations
in glioma. Although our understanding of the function of the IDH1 R132H oncoprotein has expanded
tremendously, successful exploitation of the inherent difference in 2-HG content between normal and
malignant brain tissue to improve clinical outcomes has not yet been realized. Our proposal seeks to address
this impediment to progress in two ways.
First, we aim to use 2-HG as a biomarker of IDH mutational status and optimize methodology to
quantify this metabolite non-invasively through magnetic resonance spectroscopy (MRS) imaging. We
hypothesize that MRS-generated 3D maps of 2HG concentration could be used as a complement to traditional
T2/FLAIR imaging to enable more precise delineation of tumor boundaries and yield improvements in the
efficiency of surgical resection and the quantification of therapeutic responses in glioma patients. Furthermore,
2HG 3D MRS imaging represents an ideal approach to assess pharmacodynamic responses in patients
enrolled in ongoing clinical trials of IDH targeting therapeutics.
Second, we aim to develop novel therapeutic strategies designed to preferentially eradicate IDH1
mutant glioma cells by targeting vulnerabilities engendered by high 2-HG accumulation. Pharmacological
inhibitors of mutant IDH enzymes have shown remarkable activity in IDH mutant leukemia but early clinical
data suggest that such inhibitors will be considerably less active in IDH mutant gliomas. An alternative
approach to directly targeting mutant IDH enzymes entails the exploitation of synthetic lethality with the IDH1-
R132H oncogene. We have undertaken orthogonal hypothesis-driven and screening-based approaches to
identify NAD+ metabolism and de novo pyrimidine synthesis as targetable vulnerabilities in IDH1 mutant glioma
cells. We propose to evaluate the safety and efficacy of targeting these metabolic pathways in preclinical
models of IDH1 mutant glioma to establish rationale for clinical studies of these novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10245086
- **Project number:** 5P50CA165962-08
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** WILLIAM G. KAELIN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $341,279
- **Award type:** 5
- **Project period:** 2013-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245086

## Citation

> US National Institutes of Health, RePORTER application 10245086, Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin) (5P50CA165962-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245086. Licensed CC0.

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