Mentor Name: John Prensner

Medulloblastoma, the most common malignant pediatric brain tumor, presents significant challenges when driven by MYC overexpression, which is highly aggressive and resistant to standard treatments. BET inhibitors have shown promise in reducing MYC expression. However, BET inhibitors alone are not a permanent solution, as resistance mechanisms often emerge. To improve the success of treatment, this study investigates the potential of combining BET inhibitors with Homoharringtonine (HHT), a protein translation inhibitor, to further suppress MYC levels and induce tumor cell death more effectively. This research aims to identify the optimal BET inhibitor and HHT concentration combination that maximizes tumor cell death while minimizing resistance. To achieve this, we will conduct cell viability assays using CellTiter-Glo to assess tumor cell survival across different drug concentrations. This will help determine the most potent combination for reducing medulloblastoma growth. Additionally, we will analyze apoptosis induction using flow cytometry and caspase assays to quantify programmed cell death in response to treatment. Finally, we have learned that MYC remains the most important oncogene even though BET inhibitors are supposed to get rid of MYC. We have identified sites on the MYC protein that are called phosphorylation sites and can be modified to allow the cancer cells to keep MYC active despite BET inhibitors. To gain deeper mechanistic insight, we will investigate MYC phosphosites and their role in drug response. We will create a panel of point mutations in the MYC protein that alter phosphorylation and test how these change cell response to BET inhibitors and HHT. Since post-translational modifications of MYC can influence its stability and function, identifying key phosphorylation sites may provide clues to potential resistance pathways and help refine targeted treatment strategies. By optimizing the combination of BET inhibitors and HHT, this study seeks to improve MYC-targeted therapy in medulloblastomas, offering a more effective approach to treating these aggressive tumors. Furthermore, understanding MYC phosphosite regulation could reveal new therapeutic targets, contributing to the development of more durable treatment strategies for pediatric brain tumors.