Epigenetic Targeted Therapy and Resistance in Pediatric Rhabdoid Tumor

Pediatric rhabdoid tumors in the central nervous system (CNS), atypical teratoid/rhabdoid tumors (AT/RTs), are quite possibly the most malignant and lethal of all primary brain tumors in children, and are especially devastating since their occurrence is largely restricted to very young patients. Among brain tumors, inactivating mutation of the SMARCB1 tumor suppressor is a molecular characteristic that is pathognomonic for AT/RT. The absence of SMARCB1 promotes increased EZH2 methyltransferase activity that suppresses gene transcription through increased methylation of histone H3K27. H3K27 residues are also acetylated which requires BET bromodomain protein activity. H3K27ac promotes gene transcription. The aberrant activity of these H3K27 modifiers is of fundamental importance to the occurrence of AT/RT, and each is potentially an actionable therapeutic target for treating AT/RT. This research will determine the effects of SMARCB1 activity on histone H3 post-translational modifications (PTMs) and gene expression in AT/RT, and will establish EZH2 and BRD4 activities as targets for inhibition in treating AT/RT. Using genetic and pharmacologic approaches, we will test how histone modifiers regulate gene expression in patient-derived AT/RT cells and xenograft models, and identify differentially expressed RNA transcripts and corresponding proteins that may, themselves, serve as therapeutic targets. In addition, we will study tumor adaptation to sustained EZH2 and BRD4 inhibitor treatment and identify compensatory mechanisms that will ultimately inform clinicians how to treat tumors that have acquired resistance to histone modifier therapy. Our long-term goal is to achieve improved understanding of AT/RT molecular and tumor biology in order to improve clinical outcomes for AT/RT patients via molecularly- informed treatments.