Epigenetic Targeted Therapy and Resistance in Pediatric Rhabdoid Tumor
Co-investigator: Dr. Ali Zhang
The pediatric rhabdoid tumor, atypical teratoid/rhabdoid tumor (AT/RT), is a highly-malignant brain tumor that has a poor prognosis despite aggressive treatment. The development of new, effective therapeutic approaches for AT/RT has been hindered by a lack of specific therapeutic targets. It is necessary to find effective therapeutic targets, preferably based on the understanding of the molecular mechanisms that promote this highly-malignant brain tumor. A tumor-suppressor gene (SMARCB1) is absent in the majority of AT/RT and loss of this gene leads to increased activity of histone-binding proteins and promotes tumor growth. The research involving pharmacologic inhibition of histone-binding proteins, EZH2 and BRD4, is of high importance for developing effective therapies for AT/RT. Recently published results indicate the abnormal activity of the histone binding proteins (EZH2 and BRD4) with absence of the tumor-suppressor gene (SMARCB1) is fundamental to the occurrence of AT/RT.
The goal of this project is to determine whether the therapeutic combination of targeting histone-binding proteins, BRD4 and EZH2, provides synergistic benefits. It will inform how to best maximize the clinical potential of combination therapy for effective treatment of children with AT/RT. This research will also test how tumors adapt to molecular-targeted therapy that will ultimately inform clinicians how to treat tumors that have resistance to this kind of therapy. 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 in treatment.