New Investigator Grant Awarded to Emmy Dolman

Diffuse intrinsic midline glioma (DIPG) is a rare and fast-growing brain tumor that mainly affects children. Tragically, only about 1% of children diagnosed with DIPG survive beyond five years. This is due to its location in the part of the brain that controls vital functions, making surgery impossible, and the lack of alternative effective and safe treatment options. To improve the chances of survival for children with DIPG, researchers are developing so-called precision-guided therapies (PGTs) that are customized based on the specific genetic changes in each child's tumor. However, there are significant challenges: 30% of DIPG slack genetic changes that can be targeted with available drugs, there is limited understanding of which patients will benefit from specific therapies, and
DIPGs evade the effects of single-drug treatments.

Drugs that inhibit the mitogen-activated protein kinase (MAPK) pathway are among the most frequently recommended PGTs for childhood DIPG due to the high frequency (13%) of changes in genes activating this pathway. Activation of the MAPK pathway drives the progression of DIPG. Importantly, experiments on DIPG samples from children showed that a significant subset of samples without these genetic changes were also highly sensitive to MAPK inhibitors. These included samples with changes in a gene called
phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), which activate the phosphoinositide-3-kinase (PI3K) pathway. We found that these samples also have high activity of the MAPK pathway. This suggests that the population of children with DIPG who might benefit from PGTs targeting the MAPK pathway is potentially much larger than previously recognized, offering hope to patients and families suffering from this devastating disease. In a pilot experiment, we also found that the efficacy of single MAPK inhibitors can be enhanced by combining them with an inhibitor targeting another key player in the same pathway. This approach, called vertical pathway blockade, resulted in strong synergism and improved efficacy in 70% of DIPG samples and showed superior activity over combinations targeting both the MAPK and PI3K pathways.

This collaborative project builds on this foundation to fully understand which children with DIPG will benefit from MAPK-targeting therapies and to identify the most effective and safe combinations to prevent resistance, ultimately aiming to improve survival and quality of life for children with DIPG.