Nuclear export as a therapeutic vulnerability in ZFTA-RELA ependymoma

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Abstract
Background: Ependymoma (EPN) is the third most common pediatric brain tumor with no targeted therapies available to patients. In supratentorial ependymoma, the most frequent driver alteration is a gene fusion between ZFTA and RELA (denoted ZR), 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. Methods: Using CRISPR-Cas9 pooled screening, we identified many novel druggable ZR interacting proteins including XPO1, CARM1, SMARCA4, and CDK1. We focused on the nuclear export protein (XPO1), given the ability of most XPO1 inhibitors (i.e. Selinexor) to cross the blood brain barrier, FDA approval, and documented safety profiles in children. Results: We found that specific nuclear ZR levels are needed for cell proliferation and are regulated by XPO1. Increased ZR accumulation in the nucleus does not increase oncogenic gene 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. The combination of Selinexor treatment with Gemcitabine and Ribociclib (used in a clinical trial for relapsed EPN at St Jude Children’s Research Hospital (SJDAWN)) further extends mouse survival. Conclusion: Our findings demonstrate that ZR interacting proteins constitute 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.
Funding Information
  • RCD Foundation Scientific Fellowship
  • National Brain Tumor Society
  • St. Baldrick’s Foundation Career Development
  • Matthew Larson Brain Tumor Research
  • V Scholar Translational Grant
  • St. Jude Children’s Research Hospital Research Collaborative on Transcription Regulation in Pediatric Cancer
  • Alex’s Lemonade Stand Foundation “A” Award (R01NS128184)
  • Alex’s Lemonade Stand Foundation “A” Award (R01CA280203)
  • Alex’s Lemonade Stand Foundation “A” Award (R01CA284455)
  • Alex’s Lemonade Stand Foundation “A” Award (U01CA281823)
  • Alex’s Lemonade Stand Foundation “A” Award (U01CA294103)
  • Alex’s Lemonade Stand Foundation “A” Award (CA220510)
  • DOD-IMPACT (CA220247)
  • St Jude Pediatric Dependency Map Project
  • Hartwell Center for Biotechnology
  • Center for Advanced Genome Engineering
  • National Cancer Institutes (P30 CA021765)
  • CERN Foundation
  • Robert Connor Dawes Foundation

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