biostudies-literaturePrzystal JMIsabella Kerr MolinaSwiftyNHLBI NIH HHSAl MusellaGabriella Miller Kids FirstBrad KaminskyNIHMatthew LarsonSwiss National Science FoundationKisses 4 KaylaSmashing WalnutsKortney RoseWe Love You ConnieNINDS NIH HHSChadTough Defeat DIPG1438-1451https://www.ebi.ac.uk/biostudies/studies/S-EPMC9435508biostudies-literatureUnknown24(9)<h4>Background</h4>Pediatric diffuse midline gliomas (DMGs) are incurable childhood cancers. The imipridone ONC201 has shown early clinical efficacy in a subset of DMGs. However, the anticancer mechanisms of ONC201 and its derivative ONC206 have not been fully described in DMGs.<h4>Methods</h4>DMG models including primary human in vitro (n = 18) and in vivo (murine and zebrafish) models, and patient (n = 20) frozen and FFPE specimens were used. Drug-target engagement was evaluated using in silico ChemPLP and in vitro thermal shift assay. Drug toxicity and neurotoxicity were assessed in zebrafish models. Seahorse XF Cell Mito Stress Test, MitoSOX and TMRM assays, and electron microscopy imaging were used to assess metabolic signatures. Cell lineage differentiation and drug-altered pathways Neuro-oncologyImipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas.PMC9435508R01 NS124607CRSII5-198739198739U2C HL138346U2CHL138346Laternser SMyers CCianciolo Cosentino CZhang JPrasad RVitanza NAPrzystal JMKritzer BDawood AAYadavilli SPanditharatna ENazarian JMourabit Sde Iuliis GNDun MDChin Chong WCain JEFilbin MGBonner ERLobeto NBiery MCGrotzer MAOlson JMWaszak SMKoschmann CMueller SfalseImipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas.<h4>Background</h4>Pediatric diffuse midline gliomas (DMGs) are incurable childhood cancers. The imipridone ONC201 has shown early clinical efficacy in a subset of DMGs. However, the anticancer mechanisms of ONC201 and its derivative ONC206 have not been fully described in DMGs.<h4>Methods</h4>DMG models including primary human in vitro (n = 18) and in vivo (murine and zebrafish) models, and patient (n = 20) frozen and FFPE specimens were used. Drug-target engagement was evaluated using in silico ChemPLP and in vitro thermal shift assay. Drug toxicity and neurotoxicity were assessed in zebrafish models. Seahorse XF Cell Mito Stress Test, MitoSOX and TMRM assays, and electron microscopy imaging were used to assess metabolic signatures. Cell lineage differentiation and drug-altered pathways 2022-01-01T00:00:00Z2022 Sep2026-05-27T11:05:29.621Z2025-02-19T00:14:38.692ZS-EPMC94355083515776410.1093/neuonc/noac041