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

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

doi:10.1016/j.ccell.2016.02.011

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

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. LevyMarcel Kool, Stefan M. Pfister, Michael D. Taylor, Robert J. Wechsler-Reya

Pediatric Neurology

Research output: Contribution to journal › Article

87 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	311-323
Number of pages	13
Journal	Cancer Cell
Volume	29
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2016.02.011
State	Published - Mar 14 2016

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Pei, Y., Liu, K. W., Wang, J., Garancher, A., Tao, R., Esparza, L. A., Maier, D. L., Udaka, Y. T., Murad, N., Morrissy, S., Seker-Cin, H., Brabetz, S., Qi, L., Kogiso, M., Schubert, S., Olson, J. M., Cho, Y. J., Li, X. N., Crawford, J. R., ... Wechsler-Reya, R. J. (2016). HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. Cancer Cell, 29(3), 311-323. https://doi.org/10.1016/j.ccell.2016.02.011

HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. / Pei, Yanxin; Liu, Kun Wei; Wang, Jun; Garancher, Alexandra; Tao, Ran; Esparza, Lourdes A.; Maier, Donna L.; Udaka, Yoko T.; Murad, Najiba; Morrissy, Sorana; Seker-Cin, Huriye; Brabetz, Sebastian; Qi, Lin; Kogiso, Mari; Schubert, Simone; Olson, James M.; Cho, Yoon Jae; Li, Xiao Nan; Crawford, John R.; Levy, Michael L.; Kool, Marcel; Pfister, Stefan M.; Taylor, Michael D.; Wechsler-Reya, Robert J.

In: Cancer Cell, Vol. 29, No. 3, 14.03.2016, p. 311-323.

Research output: Contribution to journal › Article

Pei, Y, Liu, KW, Wang, J, Garancher, A, Tao, R, Esparza, LA, Maier, DL, Udaka, YT, Murad, N, Morrissy, S, Seker-Cin, H, Brabetz, S, Qi, L, Kogiso, M, Schubert, S, Olson, JM, Cho, YJ, Li, XN, Crawford, JR, Levy, ML, Kool, M, Pfister, SM, Taylor, MD & Wechsler-Reya, RJ 2016, 'HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma', Cancer Cell, vol. 29, no. 3, pp. 311-323. https://doi.org/10.1016/j.ccell.2016.02.011

Pei, Yanxin ; Liu, Kun Wei ; Wang, Jun ; Garancher, Alexandra ; Tao, Ran ; Esparza, Lourdes A. ; Maier, Donna L. ; Udaka, Yoko T. ; Murad, Najiba ; Morrissy, Sorana ; Seker-Cin, Huriye ; Brabetz, Sebastian ; Qi, Lin ; Kogiso, Mari ; Schubert, Simone ; Olson, James M. ; Cho, Yoon Jae ; Li, Xiao Nan ; Crawford, John R. ; Levy, Michael L. ; Kool, Marcel ; Pfister, Stefan M. ; Taylor, Michael D. ; Wechsler-Reya, Robert J. / HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. In: Cancer Cell. 2016 ; Vol. 29, No. 3. pp. 311-323.

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abstract = "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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AU - Tao, Ran

AU - Esparza, Lourdes A.

AU - Maier, Donna L.

AU - Udaka, Yoko T.

AU - Murad, Najiba

AU - Morrissy, Sorana

AU - Seker-Cin, Huriye

AU - Brabetz, Sebastian

AU - Qi, Lin

AU - Kogiso, Mari

AU - Schubert, Simone

AU - Olson, James M.

AU - Cho, Yoon Jae

AU - Li, Xiao Nan

AU - Crawford, John R.

AU - Levy, Michael L.

AU - Kool, Marcel

AU - Pfister, Stefan M.

AU - Taylor, Michael D.

AU - Wechsler-Reya, Robert J.

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AB - 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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