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.
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.
The Children's Brain Tumor Network is contributing to this project by providing cell lines.
Carl Koschmann, MD
Dr. Koschmann is a Pediatric Neuro-Oncologist in the Department of Pediatrics and a Principal Investigator of an independent translational Pediatric Neuro-Oncology laboratory. His work in the clinic and lab complement and drive each other, resulting in a clear goal to improve therapies for childr
Michigan Medicine C.S. Mott Children’s Hospital
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective
Brainstem glioma- Diffuse intrinsic pontine glioma
A presumptive diagnosis of DIPG based on classic imaging features, in the absence of a histologic diagnosis, has been routinely employed. Increasingly however, histologic confirmation is obtained for both entry into research studies and molecular characterization of the tumor.[