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.
Update - June 2020
For a child diagnosed with an atypical teratoid rhabdoid tumor (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 does not have specific therapeutic targets that could be used to make new targeted drugs to help kids get better, based on the learning from the molecular mechanisms that drive this malignant brain tumor. We found promising characteristics of AT/RT that are epigenetic, rather than genetic, which means there are changes related to how genes are expressed by specific enzymes. We target two specific epigenetic enzymes, called EZH2 and BRD4, that appear to play an important role in the growth of AT/RT, leading to either turn off a gene that suppresses tumors or turns on a gene that enhances tumor growth. A tumor suppressor gene (SMARCB1) is absent in the majority of AT/RT and loss of this gene leads to increased activity of these epigenetic enzymes (EZH2 and BRD4) to promote tumor growth. We tested whether inhibiting EZH2 and BRD4 activity might be effective for treating AT/RT. In short, it works.
Our results showed EZH2 and BRD4 inhibitors suppress AT/RT growth in mice and increase animal survival. In addition, the combination treatment of both inhibitors showed a further decrease in tumor growth and increased survival of mice relative to either inhibitor alone. Our results inform how best to maximize the clinical potential of combination therapy for the effective treatment of children with AT/RT.
Kids with AT/RT are going to die right now. So, given this fact, the results from our research will support to create a trial using EZH2 and BRD4 inhibitors and eventually improve the outcome. We also found that tumors that initially respond to the inhibitor therapies, eventually have re-growth and become unresponsive (resistance) to the therapies in our animal study. This project also studies how tumors change gene expression patterns in response to therapy, becoming resistant to the inhibitor therapies. Eventually, this will inform clinicians on how to treat tumors that have resistance to drug treatment. We generated human AT/RT cells which have resistance to EZH2 and BRD4 inhibitors and will study how these drug-resistance tumors are different from drug-sensitive tumor using genetic and epigenetic approaches. This project will also explore how our combination therapy interacts with radiation in treating AT/RT, which is important because radiation therapy is a common treatment. Successful outcomes from this research will eventually lead to improved treatment outcomes for children with this aggressive cancer.