Pre-doctoral Fellowship Grant Awarded to Margaret Trout

Diffuse midline glioma (DMG) is notoriously resistant to chemotherapy and radiation, a key factor in its
poor prognosis. However, recent studies of the promising chemotherapeutic ONC201 implicate reactive
oxygen species (ROS) as a vulnerability in DMG. Because 90% of H2O2 is metabolized by the ROS scavenger
peroxiredoxin 3 (PRX3), we aim to evaluate whether directly targeting PRX3 is an effective strategy to kill DMG
either alone or in combination with existing therapeutic strategies. To achieve this, we aim to first characterize
PRX3 as a novel, potent vulnerability in DMG. This aim is bolstered by preliminary evidence that a PRX3
inhibitor currently in clinical trials for mesothelioma is a potent DMG killer through its ability to prevent
mitochondrial ROS scavenging. Second, we examine whether combining PRX3 inhibition with other
chemotherapies might allow for better outcomes. For example, some individuals do not respond as well to
ONC201, and eventual resistance to the drug is common. Therefore, bolstered by preliminary data, we
speculate that increasing ROS through ONC201 treatment while inhibiting ROS metabolism by PRX3 may
produce synergistic effects in DMG. Overall, my goal with these studies is to study the mechanism of PRX3
inhibition as a potential vulnerability DMG, both alone and combined with other chemotherapies. In doing so, I
aim to identify a therapeutic in DMG with high potential to be rapidly translated to patients, given the work of
our collaborators in drug discovery and advanced clinical trials for other indications.