Angela Liou, MD & Thomas De Raedt, PhD

Pediatric high-grade gliomas (pHGG) is an incurable disease. In the past, treatments have often failed because there was a lack of understanding what specific mutations and molecular pathways cause brain tumors. However, with the advent of genomic sequencing, we now understand that pHGGs often have mutations in pro-tumorigenic pathways, such as the RAS signaling pathway, and in the epigenetic machinery.

Our project explores the relationship between a well-known pro-tumorigenic pathway, RAS and the epigenetic regulator, SETD2 in the formation of pHGG. Intriguingly, both NF1 loss causing RAS pathway activation and SETD2 loss commonly occur together in pHGG, raising the question of whether there exists a link between the RAS pathway and SETD2. Indeed, we have found that RAS signaling can change SETD2’s function to potentially alter gene expression by a process called alterative polyadenylation (APA). In my proposal, we aim to further understand 1) how RAS signaling modifies SETD2 causing altered APA and gene expression in pHGG, and 2) whether the genes that undergo altered APA contribute to pHGG tumor formation. Our overarching goal is to provide the mechanistic insights that can give rise to rational and mechanism-based therapies and be able to push boundaries of treatment towards a cure for children suffering pHGG.