# Optimizing demethylating therapy for IDH1 Mutant Malignant Gliomas

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $383,606

## Abstract

Driver mutations in Isocitrate Dehydrogenase 1 (IDH1) are present in 70-80% of grade II and III gliomas, with
the majority eventually progressing to glioblastoma multiforme (GBM). In this molecularly distinct class of
malignant gliomas, mutant IDH1 enzyme produces 2-hydroxyglutarate (2-HG), an oncometabolite that inhibits
α-ketoglutarate dependent histone and DNA demethylases resulting in characteristic hypermethylation of
genomic DNA and suppression of cellular differentiation. We have demonstrated the preclinical efficacy and
mechanism of action of the approved DNA demethylating drug 5-Azacytidine (5-Aza) and revealed combinations
that further enhance survival. In models with the native IDH1 mutation, 5-Aza administration reduces tumor
burden, extends survival and induce differentiation in vivo. Combination of 5-Aza with standard of care, use of
differentiation, and pro-apoptotic drugs all show further benefit. The focus of this revised grant is to optimize
treatment and validate mechanism tailored to either grade II or high grade IDH1 mutant gliomas.
 In Aim 1 we propose to demonstrate the mechanism of 5-Aza induced cell growth reduction and further
optimize 5-Aza with standard of care treatment for IDH1 mutant glioma. We have recently demonstrated
reduction in tumor burden and extend survival in our IDH1 mutant PDX model works better when using 5-aza in
combination with temozolomide regardless of the order of administration. In Aim 2 we will determine the impact
of DNA demethylating agent in combination with differentiation therapy using retinoic acid in IDH1 mutant glioma.
Our preliminary data shows that 5-Aza regulates retinoic acid signaling, and in IDH1 mutant PDX glioma model
the two work synergistically to slow tumor growth. In aim 3 we propose to combine 5-Aza with the proapoptotic
drug PAC-1 in IDH1 mutant glioma and explore the mechanism of response. Preliminary data indicate that
Procaspase Activating Compound-1 (PAC-1), a novel brain penetrant procaspase 3 cleaving small molecule,
functions to increase apoptosis and survival in an intracranial model of IDH1 mutant glioma. Our unifying
hypothesis for each of these aims is that the combination of the mechanisms of reversing pathological
demethylation will enhance known anticancer mechanisms of DNA damage, cellular senescence and/or
apoptosis, and that interdependent mechanisms will combine to safely increase survival.
 Each of the small molecule therapies proposed show evidence of single agent efficacy in preclinical studies
for glioma. We propose to determine how the mechanisms of demethylation, differentiation therapy and caspase
3 activation best combine safely for a therapeutic response. Our major goal is to produce the preclinical data
that might support a new trial for patients with IDH1 mutant glioma. Those therapies with the possibility of causing
DNA damage will be reserved for high grade gliomas, while less toxic therapies are proposed for low grade
gliomas, where there is ...

## Key facts

- **NIH application ID:** 10329949
- **Project number:** 5R01CA190223-07
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** GREGORY Joseph RIGGINS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,606
- **Award type:** 5
- **Project period:** 2015-05-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329949

## Citation

> US National Institutes of Health, RePORTER application 10329949, Optimizing demethylating therapy for IDH1 Mutant Malignant Gliomas (5R01CA190223-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10329949. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*