# Targeting EGFR/FOXG1-mediated resistance to ONC201 in H3K27M-mutant diffuse midline glioma

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $459,296

## Abstract

PROJECT SUMMARY / ABSTRACT
Background and long-term objectives: Children and young adults with diffuse midline glioma (DMG)
harboring H3K27M mutation rarely survive longer than two years and have no proven therapies beyond
radiation. The dopamine receptor DRD2 antagonist ONC201 induces transcription of TNF-related apoptosis-
inducing ligand (TRAIL), leading to apoptosis in multiple tumor cell types. ONC201 additionally binds and
activates the mitochondrial protease ClpP, resulting in mitochondrial-mediated cell death in breast cancer cells
with active oxidative phosphorylation (OXPHOS). ONC201 is in early phase use in H3K27M-DMG, but its
mechanism and efficacy remains unknown. In our preliminary data, ONC201 is effective in murine H3 K27M-
mutant gliomas. In our unpublished clinical data (n=50 H3K27M patients), ONC201 doubles PFS and overall
survival (OS) in some clinical sub-groups (e.g. thalamic H3K27M) with multiple sustained responses. Despite
this impressive efficacy in H3K27M-DMG, we do not know how ONC201 works in H3K27M-DMG tumor cells or
how to improve responses in resistant tumors.
 In analysis of tumor sequencing, ONC201 resistance correlates with high expression of EGFR and the
brain developmental transcription factor FOXG1. FOXG1 expression is also the strongest negative predictor of
ONC201 sensitivity in human glioma cell lines. In order to prioritize which patients should be treated with
ONC201 and to generate rationale combination therapies, there is a critical need to elucidate the mechanism
of ONC201 sensitivity in H3K27M cells. Our central hypothesis is that ONC201 is effective in H3K27M-DMG
tumors with active OXPHOS through targeting of ClpP and that EGFR signaling mediates ONC201 resistance
by inactivating OXPHOS via FOXG1. This is based on our preliminary data in K27M-DMG cells, which shows
that cells cultured in media that promotes OXPHOS have an improved response to ONC201, and (iii) EGFR
knockdown reduces FOXG1 genomic binding and improves ONC201 response.
Approach: In Specific Aim 1, we will determine the impact of: (i) ClpP mitochondrial targeting vs. DRD2
antagonism and (ii) glycolysis vs OXPHOS, in the sensitivity of H3K27M-DMG cells to ONC201. In Specific Aim
2, we will determine the role of FOXG1 in H3K27M-DMG bioenergetics. In Specific Aim 3, we will determine the
ability of EGFR inhibition to impact ONC201-induced mitochondrial stress in H3K27M-DMG and for baseline
EGFR/FOXG1 tumor staining to predict ONC201 response. We expect to define the mechanism by which EGFR
and FOXG1 impact mitochondrial bioenergetics and ONC201 sensitivity in H3K27M-DMG tumors.
Significance: This contribution is expected to be significant because it will allow clinicians to prioritize which
H3K27M-DMG patients should be treated with ONC201 and provide a platform for rationale combinatorial
treatments to improve ONC201 resistance. Our translational team will soon open a multi-site international
platform trial that can implement the results...

## Key facts

- **NIH application ID:** 10771968
- **Project number:** 5R01NS124607-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Carl J Koschmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,296
- **Award type:** 5
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771968

## Citation

> US National Institutes of Health, RePORTER application 10771968, Targeting EGFR/FOXG1-mediated resistance to ONC201 in H3K27M-mutant diffuse midline glioma (5R01NS124607-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10771968. Licensed CC0.

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