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

> **NIH NIH R61** · MAYO CLINIC ROCHESTER · 2021 · $899,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10192036
- **Project number:** 1R61NS114147-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** David Daniels
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $899,750
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192036

## Citation

> US National Institutes of Health, RePORTER application 10192036, Deve inlopment of A High-Throughput Screen for Identification of Targeted Therapies in Brainstem Tumors with the H3K27M Mutation (1R61NS114147-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10192036. Licensed CC0.

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