Pre-doctoral Fellowship Grant Awarded to Sunjong Ji

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. Our group has recently demonstrated the efficacy of ONC201 in patients with H3K27M-DMG. However, not all patients with H3K27M-DMG respond to ONC201, and many patients experience recurrence while on ONC201 monotherapy. Therefore, there is a critical need to identify factors dictating response to ONC201.
Secondary analysis of genomic and transcriptomic data from ONC201-treated patients suggests that EGFR may play a role in ONC201 resistance. In turn, H3K27M-DMG cells overexpressing EGFR in vitro demonstrated increased proliferation and resistance to ONC201-induced apoptosis. Strikingly, overexpression of activating EGFR mutations in H3K27M-DMG cells in vivo led to rapid tumor growth. These data support the importance of EGFR for ONC201 resistance, making mechanistic studies of EGFR signaling in H3K27M-DMG cells crucial.
We have previously shown that ONC201 causes decreased proliferation, cell differentiation, and apoptosis.
Mechanistically, hyperactivation of mitochondrial ClpP protease by ONC201 leads to cleavage of metabolic enzymes, resulting in a metabolic profile favoring repressive H3K27me3 marks at glioma stemness and proliferation genes. Therefore, we hypothesize that EGFR confers ONC201 resistance by generating a metabolic landscape antagonizing the formation of H3K27me3. In support of this hypothesis, we have observed that EGFR-altered H3K27M-DMG cells have augmented metabolic activity, epigenetic marks, and expression of glioma stemness genes. In summary, this study will elucidate the mechanism of EGFR-mediated ONC201 resistance in H3K27M-DMG by exploring the role of EGFR in integrated metabolic and epigenetic circuits. We will also explore the potential for EGFR inhibition as a new therapeutic avenue for treatment of patients with H3K27M-DMG for whom so few therapeutic options currently exist.