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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we evaluated the preclinical therapeutic effects of ONC206 in MB and investigated its mechanism of action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noag053","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T12:45:33Z","timestamp":1772801133000},"page":"1753-1768","source":"Crossref","is-referenced-by-count":3,"title":["ONC206 demonstrates potent antitumorigenic activity and is a potential novel therapeutic strategy for high-risk 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