Targeted Inhibition of EZH2 and BET BRD4 for the treatment of AT/RT

For a child is diagnosed with an atypical teratoid rhabdoid tumor so called AT/RT, the options for treatment are scarce and so are the chances for survival. This aggressive brain tumor generally strikes children who are 5 years old and younger, with most surviving less than a year after diagnosis. AT/RT doesn’t have specific therapeutic targets that could be used to make new, targeted drugs to help kids with AT/RT get better, based on the learning from the molecular mechanisms that drive this malignant brain tumor. We found other promising characteristics of AT/RT that look like they can be targeted. These unique characteristics are epigenetic, rather than genetic, which means they are changes related to how genes are expressed (or turned on and off), rather than changes to the actual genetic code itself. In AT/RT, there are two specific epigenetic changes that we are studying. These epigenetic characteristics, called EZH2 and BRD4, appear to play an important role in the growth of AT/RT -- they help either turn off a gene that suppresses tumors or turn on a gene that enhance tumor growth, allowing AT/RT to run wild. A tumor suppressor gene (SMARCB1) is absence in the majority of AT/RT and loss of this gene leads to increase activity of histone binding enzymes BRD4 and EZH2 to promote tumor growth. Major goal of this project is to determine whether therapeutic combination of targeting two histone binding enzymes (BRD4 and EZH2) provides synergistic benefits, and will inform how best to maximize the clinical potential of combination therapy for effective treatment of children with AT/RT. This research will also test how tumor adapt to the drug therapy, that will eventually inform clinicians how to treat tumors that have resistance to drug treatment. Finally, this project will explore how our combination therapy interacts with radiation in treating AT/RT, which is important due to the frequent use of radiation therapy in treating AT/RT.