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

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Yanxin Pei, Kun-Wei Liu, Jun Wang, Alexandra Garancher, Ran Tao, Lourdes A. Esparza, Donna L. Maier, Yoko T. Udaka, Najiba Murad, Sorana Morrissy, Huriye Seker-Cin, Sebastian Brabetz, Lin Qi, Mari Kogiso, Simone Schubert, James M. Olson, Yoon-Jae Cho, Xiao-Nan Li, John R. Crawford, Michael L. Levy, Marcel Kool, Stefan M. Pfister, Michael D. Taylor, Robert J. Wechsler-Reya
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.

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Teaser

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.


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