# Dissecting the Determinants of IDH-mutant Gliomas Response to Mutant IDH Inhibitors

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $652,794

## Abstract

Abstract
This proposal focuses on IDH-mutant gliomas, a leading cause of cancer-related death in people under
45 years old. IDH mutations result in profound distortions in metabolism, chromatin structure and the
epigenetic control of gene expression. The oncogenicity of mutant IDH, together with its ubiquitous
expression across malignant cells in IDH-mutant gliomas make it an attractive therapeutic target.
However, we and others have found that the responses of IDH-mutant cancers to mutant IDH inhibitors
(IDHi) are mixed: some tumors show growth inhibition in the presence of IDHi, while others do not.
Clinically, studies in patients with progressive high-grade gliomas have shown scant signs of activity,
but recent data showed signs of objective tumor responses in subset of patients with low-grade gliomas.
The basis for this differential response in patients and in models is unknown. Our hypothesis, based
on our preliminary data, is that IDHi may act as a differentiation therapy in subsets of glioma
patients by inducing the differentiation of glioma progenitor cells towards mature glial lineages;
we further hypothesize that both intrinsic and extrinsic factors will influence the capacity of
glioma cells to respond to IDHi. To rigorously test our hypotheses, we propose (Aim 1) to perform
single-cell multi-omics analysis in a cohort of IDH-mutant gliomas with and without clinical response to
IDHi. We propose to profile IDHi-treated tumor specimen, and include matched pre- and on-treatment
sample pairs. Leveraging novel human and murine low-grade glioma models, we then suggest to
dissect how mutations associated with glioma progression (Aim 2) and how extrinsic
microenvironmental factors (Aim 3) are affecting the tumor’s response to IDHi. Altogether, this co-PI
R01 research proposal seeks to systematically dissect the neurodevelopmental, genetic and
microenvironmental cues that determine IDH-mutant glioma’s response to IDHi throughout their
progression.

## Key facts

- **NIH application ID:** 10931469
- **Project number:** 5R01CA276765-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Daniel P. Cahill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $652,794
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931469

## Citation

> US National Institutes of Health, RePORTER application 10931469, Dissecting the Determinants of IDH-mutant Gliomas Response to Mutant IDH Inhibitors (5R01CA276765-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931469. Licensed CC0.

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