Deve inlopment of A High-Throughput Screen for Identification of Targeted Therapies in Brainstem Tumors with the H3K27M Mutation

Project: Research project

Project Details

Description

PROJECT SUMMARY Pediatric high-grade gliomas including Diffuse Intrinsic Pontine Gliomas (DIPG) are aggressive brain tumors that occur in children. The lifespan for these patients after diagnosis is about one year with no cure in sight. Countless clinical trials have been performed without success and treatment remains palliative despite extensive research over the past decade. It is therefore critical to identify new therapies for these deadly diseases. Among pediatric patients, one of the most devastating brain tumor types is diffuse midline gliomas with the H3K27M mutation, which includes the previously named Diffuse Intrinsic Pontine Glioma (DIPG). Recently, somatic mutations in the H3F3A gene, one of the 16 genes that encode Histone H3, have been detected in the majority of high-grade pediatric glioma cases including DIPG. This mutation leads to an amino acid change at lysine (K) 27 residue of H3.3 to methionine (M). The H3K27M mutation is a striking example of a genetic alteration that drives tumorigenesis by modifying the epigenome. H3K27 is modified post- translationally by either acetylation or methylation. H3K27 trimethylation (H3K27me3) plays an important role in gene silencing during stem cell differentiation and maintenance. The major pathologic finding in H3K27M tumors is a global loss of H3K27me3. The changes in H3 Lysine methylation patterns dramatically change gene expression and are likely to function as drivers of malignancy in these tumors. Our goal is to develop new therapies for treating children with H3K27M tumors by developing a toolbox of primary and secondary assays and to identify small molecule compounds that increase the suppressed H3K27me3 levels in tumors with the H3K27M mutation. Our preliminary data along with others show increasing H3K27me3 leads to tumor death in H3K27M mutant tumors. Building on these exciting results we hypothesize that a disease-relevant high- throughput screening (HTS) assay can be developed and executed leading to novel therapeutic agents for brainstem tumors with the H3K27M mutation.
StatusActive
Effective start/end date6/1/215/31/23

Funding

  • National Institute of Neurological Disorders and Stroke: $899,750.00

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