HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma

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. [Display omitted] •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 MYC-driven medulloblastoma (MB) has a poor prognosis. Pei et al. report that HDAC inhibitors potently inhibit MYC-driven MB cell growth in vitro, in part by inducing the expression of FOXO1, and synergize with PI3K inhibitors to inhibit tumor growth in vivo.