EPEN-52. METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA

PFA ependymomas are a lethal glial malignancy of the hindbrain found in infants and toddlers. Lacking any highly recurrent somatic mutations, PFAs have been proposed to be a largely epigenetically driven entity, defined by hypomethylation at the histone 3 lysine 27 residue. Unfortunately, an almost complete lack of model systems has limited the discovery of novel PFA therapies. In this study, we have identified that the PFA hypoxic microenvironment controls the availability of specific metabolites, resulting in diminished H3K27 trimethylation and increased H3K27 acetylation in vitro and in vivo. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. Furthermore, perturbation of key metabolic pathways is sufficient to inhibit growth of PFA primary cultures in vitro. Although PFA tumors exhibit a low basal level of H3K27me3, inhibition of H3K27 methylation paradoxically demonstrates significant and specific activity against PFA. Thus, we propose a “Goldilocks Model” of metabolic-epigenetic regulation in PFA ependymoma, whereby increased or decreased H3K27 trimethylation results in cell death. Mapping of PFA ependymoma tumours suggests a cell of origin arising in the first trimester of human development where there is a known hypoxic microenvironment. Therefore, targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.