TMET-49. ZFTA-RELA ependymomas produce macrophage-associated itaconate as an oncometabolite to epigenetically sustain pathogenic fusion expression

Abstract ZFTA-RELA ependymomas are malignant brain tumors that are frequently lethal. They are defined by fusions formed between the putative chromatin remodeler ZFTA and the NFκB-mediator-RELA. Through a comprehensive metabolic screen, we identified that ZFTA-RELA cells produced itaconate, a TCA-cycle related metabolite. Itaconate is a key macrophage-associated immunomodulator metabolite. However, itaconate production by tumor cells and its tumor-intrinsic role are not well-established. Itaconate is synthesized by the enzyme Aconitate Decarboxylase-1 (ACOD1) and ZFTA-RELA upregulated ACOD1 in an NFκB-dependent manner. Additionally, itaconate production enabled an integrated metabolic/epigenetic feed-forward system that maintained pathogenic ZFTA-RELA fusion expression through epigenetic activation. To supply the metabolic fuel needed to generate itaconate, ZFTA-RELA tumors epigenetically activated PI3K/mTOR signaling to enhance glutaminolysis, which provided the carbons necessary for itaconate synthesis. Consequently, antagonizing glutamine metabolism lowered pathogenic ZFTA-RELA levels and was potently therapeutic in multiple in vivo models. Finally, combining glutamine antagonism with PI3K/mTOR inhibition abrogated spinal metastasis. Our data demonstrate that ZFTA-RELA ependymomas subvert a macrophage-like itaconate metabolic pathway to epigenetically maintain expression of the ZFTA-RELA fusion driver, implicating itaconate as an oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA ependymomas. This study, therefore, has implications for future drug development for children with this devastating brain tumor and will further our understanding of oncometabolites as a novel class of therapeutic dependencies in cancers.