TMET-04. ZFTA-RELA fusion supratentorial ependymomas enhance glutathione biosynthesis

Abstract Pediatric brain tumors are the leading cause of childhood cancer mortality with ependymomas being the third most common brain tumor in children. Supratentorial ependymoma (ST-EPN) is a malignant aggressive pediatric brain tumor arising in the brain hemispheres. These tumors are chemotherapy resistant, and the current standard treatments—surgical resection and radiation—are ineffective. More than 70% of ST-EPN tumors are driven by the oncogenic ZFTA-RELA fusion protein formed between the putative chromatin modifier, ZFTA, and the central NF-kB pathway regulator, RELA. Metabolic reprogramming is a cancer hallmark, and many oncogenes actively drive aberrant metabolic pathways. We performed an unbiased metabolomic screen and found that ZFTA-RELA expressing cells exhibit enhanced GSH production. Higher GSH levels help maintain redox homeostasis in tumors and drives their sustained proliferation. We treated ZFTA-RELA fusion and non-fusion cell lines with hydrogen peroxide, an oxidative stress inducer and found that ZFTA-RELA fusion cell lines were relatively resistant to oxidative stress. We also performed a proteomic screen and found key GSH biosynthesis proteins (GCLM, xCT) are upregulated in ZFTA-RELA fusion cells compared to wildtype controls. Based on this, we propose that targeting glutathione metabolism may be a therapeutic avenue for ZFTA-RELA ependymomas.