Regional Response to ONC201 in Pediatric High-Grade Glioma

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Carl Koschmann

Michigan Medicine C.S. Mott Children’s Hospital
Ann Arbor, Michigan, USA

CBTN Participants

CBTN Pre-clinical Models Used


Internal funding

About this


Pediatric High-grade glioma with H3K27M mutation (H3K27M-pHGG) carries an average overall survival of 1-2 years, and new targeted therapies are needed urgently. ONC201 is a dopamine receptor (DRD2) antagonist that is effective against H3K27M-pHGGs in pre-clinical and anecdotal clinical (case report) data. The etiology of the efficacy in H3K27M-pHGGs has not been explained, and no previous work has studied the impact of regional brain micro-environment of midline structures (brainstem vs thalamus) on ONC201 response. We have conducted an ongoing integrated clinical analysis of adult and pediatric patients treated on multiple early phase clinical trials to assess the regional (brainstem vs thalamus) response to treatment with ONC201 in H3K27M-pHGG. Surprisingly, patients with thalamic-H3K27M-HGG (adult and pediatric, n=29) demonstrated an exceptional response to ONC201. Excitingly, the current estimates for progression free survival (PFS) and overall survival (OS) are better than any previously seen. In this project our goal will be to study the mechanism of regional (brainstem vs thalamus) response to ONC201 in pre-clinical models of H3K27M-pHGG. Our current hypothesis is that regional DRD2 contributes to the exceptional response in thalamic H3K27M-pHGG.

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What are the goals of this project?

The goals of this project are to perform ONC201 treatment, terminal perfusion and tumor fixation/analysis of orthotopically-implanted pHGG neurospheres cells in various regions of the mouse brain, perform immuno-histochemistry (IHC) analysis of dopaminergic signaling and markers of the integrated stress response in these tumor, treat human cells from brainstem and thalamic-pHGG-H3K27M (in vitro) with ONC201 (in vitro), to assess regional effects on efficacy and to assess impact of dopaminergic signaling on different locations of the brain (with addition of dopamine agonist and perform IHC analysis of dopaminergic signaling (e.g. DRD2 and TH) in human pediatric HGG-K27M tumors (thalamus and brainstem) and compare to expression in non-tumor pediatric brain samples.

What is the impact of this project?

Our integrative experimental approach will establish the mechanism behind the phenotypes we have recently discovered and open new windows for therapies targeted to H3K27M-mutant pediatric HGG.

Why the CBTN request is important to this project?

The pHGG cell lines with annotated molecular and regional information are critical resources to answer our pre-clinical questions.

Specimen Data

The Children's Brain Tumor Network is contributing to this project by providing cell lines.