Metabolic Therapies for Childhood Posterior Fossa Group-A
Mentor Name: Sriram Venneti
Posterior fossa-group A (PFAs) represent the most common form of childhood ependymoma and bear dismal prognoses due to a lack of effective treatment options. PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), which causes a reduction in the repressive histone methylation mark H3K27me3 and alters gene expression. However, the mechanisms by which EZHIP promotes PFA oncogenesis remain unclear. Our lab has recently demonstrated that EZHIP can epigenetically reprogram key metabolic pathways including glycolysis and tricarboxylic citric acid (TCA) cycle metabolism. We show that EZHIP causes upregulation of the TCA cycle enzyme isocitrate dehydrogenase 1 (IDH1) resulting in elevated levels of aKG in PFAs. We hypothesize that IDH1 expression increases aKG production, which is required by histone demethylases to maintain low H3K27me3 in PFAs. Further, we hypothesize that inhibiting IDH1 will be therapeutic by reducing aKG levels and restoring H3K27me3 marks in PFAs. These data will provide novel insight into the mechanisms that drive EZHIP-mediated oncogenesis and shed light on therapeutic vulnerabilities in PFAs.
