New Investigator Grant Awarded to Matthew Waitkus

Diffuse midline gliomas, H3K27M-mutant (DMG-H3K27M) are a type of lethal pediatric brain tumor. These tumors are resistant to conventional therapies and generally not amenable to surgical resection due to their location in sensitive areas of the brain. For these reasons, new therapies that efficiently and specifically kill DMG-H3K27M cells are urgently needed. Although H3K27M mutations are understood to be a primary driver of DMG-H3K27M tumor growth, we do not fully understand how these mutations cause tumors to form, and the optimal strategies for therapeutically targeting these mutations to effectively kill DMG-H3K27M tumor cells are not yet understood. The overarching objective of this proposal is to determine the therapeutic potential of inhibiting an enzyme involved in DNA repair, SMARCAL1, for DMG-H3K27M therapy in pre-clinical models. SMARCAL1 has not yet been investigated as a therapeutic target in DMG-H3K27M tumors. Our preliminary data indicate that inducible depletion of SMARCAL1 in DMG-H3K27M cells leads to DNA damage, suppression of proliferation, prolonged survival of mice bearing intracranial DMG-H3K27M tumors, and the induction of tumor-intrinsic inflammation. Based on these data, we will investigate the therapeutic potential of inhibiting SMARCAL1 as a novel therapeutic strategy for the treatment of DMG-H3K27M tumors. Results from these studies will provide an evidence-based pre-clinical justification for the development of SMARCAL1-targeting drugs and provide important data to guide the design of clinical studies targeting DNA replication stress in DMG-H3K27M tumors.