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

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $498,788

## Abstract

Our laboratories recent studies (Stegh and colleagues, Ce// 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 genetic and pharmacological inhibition of wt-lDH1, alone and in combination with radiation therapy (RT) slows the growth of patient-derived HGG xenografts5,6, while overexpression of wt-lDH1 promotes intracranial HGG growth. On molecular levels, wt-lDH1high 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 phospholipid peroxidase glutathione peroxidase 4 (GPX4)-driven lipid repair, and dampens the accumulation of polyunsaturated fatty acid (PUFA)-containing lipid peroxides, known executioners of ferroptosis.
Based on these findings, we hypothesize that wt-lDH1 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-lDH1, we have used and characterized 13i, a first-in­ c/ass competitive a,f]-unsaturated enone, developed by AbbVie. 13i potently inhibits wt-lDH1 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-wfhigh HGG bearing mice, alone and in combination with RT. We will test these hypotheses in three Specific Aims:
Aim 1: Determine how wt-lDH1 impacts de novo fatty acid biosynthesis and membrane phospholipid composition to inhibit ferroptosis.
Aim 2. Determine how wt-lDH1 promotes GPX4-dependent lipid repair and antagonizes ferroptosis.
Aim 3: Determine if genetic and pharmacological inactivation of wt-lDH1 amplifies ferroptosis in response to RT and immune checkpoint blockade and antagonizes HGG progression.
Objectives and long-term goals. We will credential wt-lDH1 as regulator of ferroptosis in HGG and will validate the pharmacological inhibition of wt-lDH1 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:** 10539153
- **Project number:** 1R01NS129123-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Alexander H. Stegh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $498,788
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539153

## Citation

> US National Institutes of Health, RePORTER application 10539153, Inhibition of wild-type IDH1 as a ferroptosis-inducing therapeutic approach for the treatment of malignant glioma. (1R01NS129123-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10539153. Licensed CC0.

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