# Project 4: Novel epigenetic treatment of IDH mutant gliomas

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $351,815

## Abstract

Project 4: Novel epigenetic treatment of IDH mutant gliomas
SUMMARY/ABSTRACT
Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in several cancer types, including the majority
of low-grade gliomas and secondary glioblastomas (GBM). Although their survival is relatively prolonged
relative to patients with wild-type IDH, patients with IDH mutant gliomas still almost invariably succumb to their
disease. Mutant IDH causes the aberrant production of the oncometabolite D-2-hydroxyglutarate (2HG). How
2HG contributes to glioma formation is not well-understood, but it is postulated that 2HG interferes with a
number of α-ketoglutarate dependent enzymes, including those involved in DNA demethylation. A number of
lines of evidence indicate that inactivation of the demethylator TET2 could result in the DNA hypermethylation
observed in many IDH mutant tumors. Treatment with selective inhibitors of mutant IDH have shown promise
in acute myelogenous leukemia (AML), but results of pre-clinical studies in glioma have been mixed. Our
preliminary data indicate that the transcription factor OLIG2 may be responsible for downregulating TET2
mRNA which, in combination with 2HG, potentially renders TET2 activity virtually non-existent in IDH1-mutant
gliomas. As such, inhibition of mutant IDH alone would be insufficient to recoup TET2 function. It is our
fundamental hypothesis that IDH mutant gliomas are dependent on repression of TET2 expression and
function, and that a combined approach of inhibition of the enzymatic function of mutant IDH along with the
suppression of OLIG2 will have a beneficial effect on the treatment of IDH mutant gliomas. In Aim 1, we will
validate the importance of OLIG2 in IDH mutant gliomas, using CRISPR-based gene editing in vitro and in
vivo. These experiments will also determine whether IDH mutant gliomas with different background mutations,
e.g., P53 mutation or 1p/19q deletion, will have different dependency on OLIG2. In Aim 2, we will then
determine whether disruption of OLIG2 alone and in combination with inhibition of mutant IDH1 function --
using the investigational compound AG-881 (a novel brain-penetrant pan-IDH mutant inhibitor) -- disrupts
TET2 function and inhibits tumor growth. Since direct small molecule inhibitors of OLIG2 have not been
developed, our clinical strategy will focus on the use of the FDA-approved histone deacetylase (HDAC)
inhibitor, panobinostat to downregulate OLIG2. In pre-clinical studies, we will test the effects of panobinostat
and other HDAC inhibitors with and without AG-881 on OLIG2 expression and TET2 function, as well as on
growth of IDH mutant tumors in vitro and in vivo. In Aim 3, we will then proceed with a 2-stage clinical study. In
the first stage, we will perform a pharmacokinetic/pharmacodynamic clinical trial to verify the effects of
panobinostat on OLIG2 expression in patients with IDH mutant tumors. In the second stage, we will conduct a
Phase II randomized clinical trial comparing ...

## Key facts

- **NIH application ID:** 9983050
- **Project number:** 5P50CA211015-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** HARLEY IAN KORNBLUM
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,815
- **Award type:** 5
- **Project period:** 2017-08-11 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983050

## Citation

> US National Institutes of Health, RePORTER application 9983050, Project 4: Novel epigenetic treatment of IDH mutant gliomas (5P50CA211015-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983050. Licensed CC0.

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