High-throughput screening identifies inhibitors of MYC-driven MB
•
HDACIs inhibit growth of murine and human MYC-driven MB cells
•
HDACIs and PI3KIs cooperate to activate FOXO1 and suppress tumor growth in vitro
•
HDACIs and PI3KIs inhibit growth of MYC-driven tumors in vivo
Summary
Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MYC-driven MB has a particularly poor prognosis and would greatly benefit from more effective therapies. We used an animal model of MYC-driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACIs). HDACIs potently inhibit survival of MYC-driven MB cells in vitro, in part by inducing expression of the FOXO1 tumor suppressor gene. HDACIs also synergize with phosphatidylinositol 3-kinase inhibitors to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB.