Diffuse Midline Gliomas (DMGs) are a uniformly fatal pediatric brain cancer - surgically inaccessible and refractory to radiation or chemotherapy. The prevalent oncogenic drivers for DMG (80 % of cases) are a set of recurrent K27M substitutions in histone H3 gene. H3K27M DMGs are confined to a narrow anatomical region of the brain, and arise within a narrow developmental window of time. This spatial/temporal restriction suggests that antagonists of H3K27M function might have a broad therapeutic window for DMG. However, H3K27M oncoproteins have no intrinsic enzymatic activity and thus do not lend themselves to development of small molecule antagonists. Various workarounds are in progress but have yet to yield any clinical benefit for children with DMG.<br/>Towards “drugging the undruggable” for this lethal pediatric brain cancer, we have completed a large CRISPR-based negative-selection screen for downstream effectors of H3K27M function. This screen showed that DMGs are dependent upon multiple chromatin regulators, polycomb repressive complexes, histone demethylases, acetyltransferases and deacetylators. In accord with the spatial/temporal specificity of H3K27M cancers, the requirement for most of these epigenetic targets is cell type and developmental stage-specific rather than pan essential. Excitingly, a few chromatin regulators may also lend themselves to novel drug development. Towards the long-term goal of a brain-penetrant antagonist of H3K27M function, we now focus on structure/function relationships of chromatin regulators within H3K27M DMG, as well as on identifying synergistic combinations of epigenetic drugs.

Targeting epigenetic vulnerabilities in histone mutant pediatric high-grade glioma

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.