Game Changer Grant Awarded to Matt Dun

Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), is a lethal pediatric brain tumor responsible for 20–25% of pediatric cancer deaths. Median survival is just 9–11 months, and the 5-year survival rate is below 1%. Current treatment is limited to palliative radiation. Drugs such as ONC201 and paxalisib have shown promise in animal models of DIPG and, when administered in combination as a
consolidation strategy post re-irradiation therapy in the recent PNOC022 trial, extended survival of DIPG patients by an additional 8.8 months. However, this survival benefit was only seen when the drugs were administered at cancer progression, and not when the same treatment strategy was used at initial diagnosis. The reasons for this disparity remain unclear but may involve immune-related factors, metabolomic changes, or challenges with drug distribution.

In this project, we will analyze tumor tissues from DIPG patients (including those in the PNOC022 trial) using our advanced “spatial multiomics” platform. These spatial analyses will assess drug distribution, quantifying concentrations in specific types of brain and tumor cells in the biopsy. They will also assess immune activity and metabolomic impacts of the drugs, allow identification of responsive cell populations and resistance mechanisms, and provide deeper insights into treatment response. Additionally, we will use cutting-edge spatial protein assays to confirm new drug targets and the brain cells most affected by treatment and to identify potential novel non-invasive protein biomarkers of response and failure. This research will establish a robust pipeline for evaluating drug penetration and drug-induced metabolomic and gene expression changes in DIPG patient biopsies. By informing trial design, optimizing sequential strategies, and refining therapy dosing, this pipeline creates a foundation for future trials and brain cancer research, with the ultimate aims of extending survival and improving
quality of life for DIPG patients. The project will help us learn from the past to improve the future for other DIPG patients.