Targeting integrated metabolic and epigenetic pathways in childhood ependymomas

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Ependymomas in children mainly arise in the hindbrain/ posterior fossa (PF) and carry high morbidity and mortality. Despite decades of clinical trials, mainstay treatment still remains surgery and adjuvant radiation, that are not curative. PF ependymomas are unique as more than 80% of tumors do not bear recurrent genetic alterations. Instead, they are epigenetically driven. They are classified into group-A (PFAs) tumors defined by an epigenetic state of global reduction of the repressive mark H3K27me3 and group-B (PFBs) tumors that do not show a reduction in H3K27me3. PFAs mainly occur in infants and young children and exhibit a dismal prognosis, while PFB tumors are mainly observed in adolescents and adults and bear an excellent prognosis. Reduced H3K27me3 in PFAs is mediated by a protein termed EZHIP (EZH inhibitory protein) that suppresses the function of the H3K27 methyltransferase EZH2. However, how EZHIP drives the pathogenesis of PFAs remains unknown. A central hallmark of cancer is reprograming of cellular metabolism by oncogenes, which enables increased uptake and metabolism of nutrients such as glucose by tumors. Moreover, Metabolic and epigenetic pathways are intimately linked and metabolites can directly impact epigenetic modifications. For example, the metabolite α-ketoglutarate (αKG) is a critical cofactor for the H3K27 histone lysine demethylases (KDMs) that can drive global reduction of H3K27me3. Our preliminary data show that EZHIP enhances glycolysis and TCA cycle to produce high αKG levels. Our overarching hypothesis is that EZHIP epigenetically rewires cellular metabolism to increase αKG production that is required to maintain low H3K27me3 levels. Consequently, suppressing this epigenetic/ metabolic pathway will be therapeutic. Two specific aims will address our hypothesis: Aim 1. Elucidate the molecular mechanisms by which EZHIP enhances glycolysis and TCA cycle metabolism. Aim 2. Determine the therapeutic potential of targeting an integrated metabolic/ epigenetic pathway to combat these tumors. The combination of these two aims will address significant gaps in our understanding of PFAs and lay the groundwork to develop effective treatments.