MDB-24. Integrated metabolic and epigenetic therapies for Group-3 Medulloblastomas

Abstract We sought to delineate, and target integrated metabolic and epigenetic pathways in cMYC-driven Group-3 medulloblastoma (MB). In a comprehensive screen, we identified upregulation of wild type isocitrate dehydrogenase 1 (IDH1) in Group-3 MB. Surprisingly, genetic and pharmacologic targeting of IDH1 reduced cMYC expression levels and was therapeutic in three independent (patient-derived D283, p = 0.0004; D341, p = 0.0008 and syngeneic murine Group-3 MB p = 0.0005) Group-3 MB animal models in vivo, but not in non-group 3 ONS76 animals (p = 0.1771). Mechanistically, IDH1 inhibition epigenetically suppressed cMYC expression by increasing repressive methylation marks at the cMYC locus. Additionally, we noted that IDH1 inhibition triggered a novel copper-dependent form of cell death termed cuproptosis. This mechanism was via cMYC-dependent downregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC). Forced in vivo increase in tumor cellular copper levels by treating with Elesclomol, a blood-brain-barrier penetrant copper ionophore reduced tumor burden and increased overall survival in three independent (patient-derived D283, p = 0.0009; D341, p = 0.0188 and syngeneic murine Group-3 MB p = 0.0002) Group-3 MB animal models in vivo, but not in non-group 3 ONS76 animals (p = 0.1307). Our work establishes an integrated metabolic/epigenetic pathway driven by wild type IDH1 which serves as a gatekeeper to regulate cMYC expression and downstream copper metabolism in Group-3 MB. This novel pathway can be therapeutically leveraged using the blood-brain-barrier penetrant copper ionophore elesclomol that is currently in clinical trials for adult cancers.