# Inhibition of wild-type IDH1 as a ferroptosis-inducing therapeutic approach for the treatment of malignant glioma.

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $474,236

## Abstract

Our laboratories recent studies (Stegh and colleagues, Cell Report, 2017; Wahl and colleagues, Cancer
Research, 2017) indicated that IDH1 wild-type (IDH1-wt) is overexpressed in 2/3 of HGG (referred to here
as `IDH1-wthigh GBM') that lack IDH1R132H mutation. Both
alone
while
genetic and pharmacological inhibition of wt-IDH1,
and in combination with radiation therapy (RT) slows the growth of patient-derived HGG xenografts 5,6
overexpression of wt-IDH1 promotes intracranial HGG growth molecular levels, wt-IDH1 high
,
. On GBM
produce excess NADPH, which serves as a rate-limiting reductant that drives the biosynthesis of mono-
unsaturated fatty acids (MUFAs). In addition, enhanced NADPH production increases glutathione (GSH)
level, reduces reactive oxygen species (ROS), activates phospholipidperoxidase glutathione peroxidase 4
(GPX4)-drivenlipid repair, and dampensthe accumulation of polyunsaturated fatty acid (PUFA)-containing
lipid peroxides, known executioners of ferroptosis.
Based on these findings, we hypothesize that wt-IDH1 through enhanced lipid repair, heightened MUFA
biosynthesis and displacement of oxidizable PUFAs from plasma membrane phospholipids antagonizes
ferroptosis, a recently discovered form of cell death has rapidly gained recognition as a paradigm shifting
strategy to specifically target cancer cells. We further hypothesize that wt-IDH1 inhibition cooperates with
known inducers of ferroptosis, including RT and immune-mediated checkpoint inhibition, to antagonize HGG
progression. For the pharmacological inhibition of wt-IDH1, we have used and characterized 13i, a first-in-
class competitive ???-unsaturated enone, developed by AbbVie. 13i potently inhibits wt-IDH1 enzymatic
activity, by covalently binding to the NADP+ binding pocket. Our data indicate that 13i promotes ferroptosis,
is brain-penetrant, and like genetic ablation, reduces progression and extends the survival of IDH1-wthigh
HGG bearing mice, alone and in combination with RT. We will test these hypotheses in three Specific Aims:
Aim 1: Determine how wt-IDH1 impacts de novo fatty acid biosynthesis and membrane phospholipid
 composition to inhibit ferroptosis.
Aim 2. Determine how wt-IDH1 promotes GPX4-dependent lipid repair and antagonizes ferroptosis.
Aim 3: Determine if genetic and pharmacological inactivation of wt-IDH1 amplifies ferroptosis in
 response to RT and immune checkpoint blockade and antagonizes HGG progression.
Objectives and long-term goals. We will credential wt-IDH1 as regulator of ferroptosis in HGG and will
validate the pharmacological inhibition of wt-IDH1 using a novel NADP+ competitive inhibitor as a therapeutic
strategy. Results from these studies are expected to inform the design of IND-enabling studies evaluating
the potential of 13i as adjuvant for anti-HGG therapy.

## Key facts

- **NIH application ID:** 10896303
- **Project number:** 5R01NS129123-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Alexander H. Stegh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $474,236
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896303

## Citation

> US National Institutes of Health, RePORTER application 10896303, Inhibition of wild-type IDH1 as a ferroptosis-inducing therapeutic approach for the treatment of malignant glioma. (5R01NS129123-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10896303. Licensed CC0.

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