EXTH-74. Nuclear Transport as a Therapeutic Vulnerability in ZFTA-RELA Ependymoma

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Abstract Ependymoma (EPN) is the third most common pediatric brain tumor with no targeted therapies available to patients. The most frequent driver alteration is a gene fusion between ZFTA and RELA (denoted ZR), which leads to constitutive localization of ZR in the nucleus. Because ZR is not currently druggable, we tested whether ZR expression leads to aberrant protein interactions that could represent therapeutic vulnerabilities. Using CRISPR-Cas9 pooled screening, we identified many novel druggable targets of ZR-interacting proteins, including Xpo1, Carm1, Smarca4, and Cdk1. We focused on the nuclear export protein (Xpo1), given the ability of Xpo1 inhibitors (i.e. Selinexor) to cross the blood brain barrier, FDA approval, and documented safety profiles in children. We found that specific nuclear levels of ZR are needed for cell proliferation, and it’s regulated by Xpo1. Increased ZR accumulation does not increase oncogenic expression but drives tumor cells out of cell cycle, as compared to a defective ZR DNA binding mutant. Treatment of ZR-driven patient-derived mouse models with Selinexor impairs cell growth and extends survival of animals in vivo, in a disease subtype specific manner. The combination of Selinexor treatment with Gemcitabine and Ribociclib (currently in clinical trials for EPN at St Jude Children’s Research Hospital (SJDAWN)) further extends mouse survival. Our findings demonstrate that ZR-interacting proteins contain therapeutic leads, and that Xpo1 is critical for titrating ‘goldilocks’ levels of ZR nuclear expression. We identify a novel combination therapy of Selinexor, Gemcitabine, and Ribociclib that may be immediately translated into clinical trials for EPN patients that are currently without targeted treatments.

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