MODL-02. ONC206 inhibits tumor growth and is a potential novel therapeutic strategy for refractory medulloblastoma

Abstract Medulloblastoma is the most common malignant pediatric brain tumor with 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). ONC206 is currently in Phase I clinical trials for pediatric patients with primary brain tumors. In this study, we evaluated the preclinical therapeutic effects of ONC206 in medulloblastoma in vitro and in vivo and investigated its mechanism of action. We found evidence for high expression of ClpP at both the RNA and protein level in medulloblastoma 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 SHH-driven and Group 3 medulloblastoma cells treated with ONC206 with low IC-50s (range: 14nM - 2μM). After treatment with ONC206, we observed a significant downregulation of mitochondrial electron transport chain complexes, as well as an induction of the ATF4 pathway, thereby implying that ONC206 induces an integrated stress response and mitochondrial damage. To test the efficacy of ONC206 in vivo, we used murine models of SHH-driven and Group 3 medulloblastoma as well as Group 3 and Group 4 patient-derived xenografts (PDXs). ONC206 led to a significant prolongation of survival in both murine models (p = 0.007 for Group 3 and p = 0.006 for SHH), with the SHH mice demonstrating a doubling of survival from 70 to 140 days. PDX-bearing mice also responded to ONC206, which led to a significant survival benefit (p-value range 0.003-0.047). Our results highlight ONC206 as a novel therapeutic option for patients with relapsed medulloblastoma and provide strong rationale for testing the efficacy of ONC206 in the treatment of these patients.