# Project 2: Druggable dependencies in diffuse midline gliomas

> **NIH NIH P50** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $487,885

## Abstract

Project Summary
We propose a SPORE project on diffuse midline glioma (DMG)--a uniformly fatal glioma occurring mainly in
children. The prevalent oncogenic drivers for DMG are a set of recurrent amino acid substitutions in histone H3
(H3.3 and H3.1), wherein lysine 27 is mutated to methionine [H3K27M]. The mutated histones have no
enzymatic function and are thus completely undruggable. Various workarounds, including histone deacetylase
inhibitors and immunotherapy, are being developed but have yet to show clear benefit for DMG patients.
 Against this backdrop, during the current funding period of this SPORE, we conducted a genome-wide
CRISPR screen for DMG metabolic vulnerabilities. Our screen (Pal et al, Cancer Cell 2023) showed that
DMGs are “addicted” to the alternative end-joining (alt-EJ) pathway for repair of DNA double-strand breaks.
We identified a trio of clinical-stage, brain-penetrant drugs that target this addiction in complementary ways by
suppressing separate components of the alt-EJ pathway. Finally, we performed all pre-clinical requisite studies
for one of these drugs (orludodstat--a DHODH antagonist) towards support of a clinical trial trial in this project.
Our study plan builds upon this preliminary work and has three hypothesis-driven specific aims:
 Aim 1 will test the hypothesis that pre-clinical findings with orludodstat can be recapitulated in children with
DMGs. To test this hypothesis, we will conduct a lead-in phase 1 trial of orludodstat, followed by a phase 0/
target validation arm, in children with H3K27M DMG. We note that this pediatric trial will complement a trial
with the same drug for grade 2 IDH-mutant astrocytomas of young adults being developed by the Project 3
team of this SPORE. Aim 2 will test the hypothesis that our alternate drugs for suppression of alt-EJ (POLQ
and ATR antagonists) will prove efficacious as single agents and in combinatorial regimens to overcome innate
or acquired resistance to DHODH inhibition. Aim 3 will test the hypothesis that suppression of alt-EJ will enrich
for specific tumor cell subsets and stromal cell types in DMG patients. As a tool to test this hypothesis, we will
assemble a 3D reference map of DMG tumor cells, partially differentiated DMG subtypes, and normal stroma
using recently developed “spatial transcriptomic” technology from Dr. Filbin and her team.
 The study plan is enabled by an interactive collaboration among four investigators whose skillsets exceed
the sum of their component parts. Dr. Daphne Haas-Kogan is a physician-scientist with much practical
experience in clinical care of children with DMG. Basic scientist, Dr. Mariella Filbin, Scientific Director of the
Pediatric Brain Tumor Center, Boston Children’s Hospital, is a leader in single cell genomic analylis of pediatric
brain tumors. Dr. Sabine Mueller is an expert on design and conduct of clinical trials and leads the Pacific
Pediatric Neuro-Oncology Consortium (PNOC). Dr. Nathalie Agar provides specialized...

## Key facts

- **NIH application ID:** 10935603
- **Project number:** 2P50CA165962-11
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** DAPHNE A. HAAS-KOGAN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $487,885
- **Award type:** 2
- **Project period:** 2013-09-19 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935603

## Citation

> US National Institutes of Health, RePORTER application 10935603, Project 2: Druggable dependencies in diffuse midline gliomas (2P50CA165962-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10935603. Licensed CC0.

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