# Exploiting the vulnerabilities in mutant IDH gliomas

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $333,594

## Abstract

With incidence rates up to 80%, isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in
grade II-III gliomas and secondary glioblastomas. Prior to its discovery in gliomas by Parsons et al. in 2008,
this mutation had never before been linked to cancer. Subsequent studies have identified IDH1 and IDH2
mutations in several different tumor types suggesting that these genes are important players in cancer. The
mechanism by which mutant IDH promotes tumor development has been under intense investigation and
several key findings have significantly improved our understanding of the biology of this disease. IDH proteins
function to generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) from NADP+ by
catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). These mutations inhibit the
native function of the enzyme and instead confer a gain-of-function phenotype resulting in the conversion of α-
KG to 2-hydroxyglutarate (2-HG). 2-HG is a competitive inhibitor of multiple α-KG-dependent enzymes,
including transaminases, histone demethylases, and the TET family of 5-methylcytosine hydroxylases, which
mediate DNA demethylation. As a result, gliomas harboring mutations in IDH exhibit increased dependence on
glutaminase, defects in DNA repair, and manifest a DNA hypermethylation phenotype. Mutant IDH also
compromises the citric acid cycle, which results in an enhanced dependence on mitochondrial metabolism.
Interestingly, the presence of an IDH mutation was found to be an independent marker for better prognosis and
it was discovered that tumors harboring mutations in IDH are more sensitive to conventional chemotherapy
and radiotherapy. As such, we hypothesize that tumors harboring mutations in IDH have multiple vulnerabilities
that can be therapeutically exploited. However, evaluating these strategies has been hindered by the lack of
appropriate in vivo models. To fill this void, we developed a mouse model of mutant IDH1-driven glioma that
mimics the human disease genetically, functionally, and histologically. Our results support the hypothesis that
mutant IDH1 is a bona fide glioma oncogene and provide the first in vivo evidence that it promotes
gliomagenesis. The model we have developed is ideal for assessing rational therapeutic strategies to combat
this disease. In this study, we propose to use human glioma cells and our novel mouse models to evaluate the
sensitivity of these gliomas to DNA demethylating agents in combination with mutant IDH1 inhibitors, to exploit
their dependence on glutamine metabolism, and to target their enhanced requirement for oxidative
phosphorylation. Demonstration of therapeutic efficacy in our novel glioma mouse model will further support
translation to the clinic and has the potential to significantly improve the outcome for patients with this deadly
disease.

## Key facts

- **NIH application ID:** 9910471
- **Project number:** 5R01NS107810-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Sheri L Holmen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,594
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910471

## Citation

> US National Institutes of Health, RePORTER application 9910471, Exploiting the vulnerabilities in mutant IDH gliomas (5R01NS107810-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9910471. Licensed CC0.

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