Epigenetic targeting and adaptation of EZH2 and BET BRD4 in AT/RT

Atypical teratoid/rhabdoid tumors (AT/RTs) are quite possibly the most malignant and deadliest of all brain tumors in children, and are especially devastating since their occurrence is largely in very young patients. Among brain tumors, specific mutation of a tumor suppressor gene (SMARCB1) is a molecular characteristic for AT/RT, and that changes a function of DNA binding protein, histone, and histone modification protein (EZH2). The mutation of tumor suppressor (SMARCB1) leads to increase activity of EZH2 histone modification protein, that changes other tumor suppressor gene activity resulted in increased tumor growth. In addition, recent study found that histone binding protein (BET bromodomain protein) is necessary to support the tumor growth, and provides rational therapeutic target for the treatment of AT/RT. This project will study how histone modifications and gene expression changes effect on AT/RT growth, and how genetic/pharmacologic inhibition of histone binding proteins (EZH2 and BRD4) activity affect the growth of AT/RT. In addition, we will study adaptation of tumor cell to drug treatment (i.e. EZH2 inhibitor and BRD4 inhibitor) and identify drug resistance mechanisms that will ultimately inform clinicians how to treat tumors that have acquired resistance to molecular targeted 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 via molecularly-informed treatments.