ONC206 demonstrates potent antitumorigenic activity and is a potential novel therapeutic strategy for high-risk medulloblastoma

BACKGROUND: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and has an urgent need for novel treatment approaches. Dordaviprone (ONC201) and its chemical derivative with nanomolar potency, ONC206, induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). Dordaviprone is currently in phase I clinical trials for pediatric patients with primary brain tumors. METHODS: In this study, we evaluated the preclinical therapeutic effects of ONC206 in MB and investigated its mechanism of action. RESULTS: We found evidence for high expression of ClpP at both the RNA and protein level in MB tumors, compared to very low expression in normal brain tissue. In addition, we saw a pronounced reduction in cell viability of human group 3 and group 4 and murine Sonic-Hedgehog-activated (SHH)-driven and group 3 MB cells treated with ONC206 with low IC-50s. After treatment with ONC206, we observed an induction of integrated stress response and mitochondrial damage. To test the efficacy of ONC206 in vivo, we used murine models of SHH-driven and group 3 MB as well as group 3 and group 4 patient-derived xenografts (PDXs). Dordaviprone led to a significant prolongation of survival in both murine models, with the SHH mice demonstrating survival extension from 70 to 140 days. Patient-derived xenograft-bearing mice also responded to ONC206, which led to a significant survival benefit. CONCLUSION: Our results highlight ONC206 as a novel therapeutic option for patients with high-risk MB and provide strong rationale for testing the efficacy of ONC206 in the treatment of these patients.