Investigating the role of BAI1 in the Metastasis of Medulloblastoma
Medulloblastoma (MB) is the most common pediatric brain tumor. MB cells commonly escape from the primary tumor, spread to the surface of the brain and in the spinal cord where they grow and form metastatic tumors, which cause patient death. Although we know a lot about primary MB, little is known about the mechanisms of metastasis. Currently, there are no effective therapies to inhibit MB metastasis; therefore, their molecular analysis is needed to develop new effective therapies. I found that BAI1, a tumor suppressor, is highly suppressed in MB by epigenetic silencing through EZH2. Low BAI1 is associated with poor prognosis of MB patients and increases MB cell metastasis in a murine model. Furthermore, I showed that BAI1 regulates the activity of TGFβ1 signaling, an important factor controlling metastasis in other cancers.
In this proposal, I plan to define how BAI1 interrupts TGFβ1 signaling. I will reactivate BAI1 using EZH2 inhibitor, EPZ6438, in MB cells, and evaluate whether it reduces MB metastasis in murine models. The role of BAI1 in MB metastasis has never been examined, making my research novel and innovative. My studies will provide proof-of-principle data to determine whether new epigenetic therapies can prevent or reduce metastasis in the pediatric patients with MB. EPZ6438 is clinically safe and is currently being tested in patients with other cancers in phase II clinical trials; hence, my findings could be rapidly translated in pediatric patients with MB. As a physician-scientist, my goal is to lead my independent research program with a focus on translational pediatric neuro-oncology.