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

Research output: Contribution to journal › Article › peer-review

192 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
Externally published	Yes

ASJC Scopus subject areas

Oncology
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

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

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title = "HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma",

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.",

author = "Yanxin Pei and Liu, {Kun Wei} and Jun Wang and Alexandra Garancher and Ran Tao and Esparza, {Lourdes A.} and Maier, {Donna L.} and Udaka, {Yoko T.} and Najiba Murad and Sorana Morrissy and Huriye Seker-Cin and Sebastian Brabetz and Lin Qi and Mari Kogiso and Simone Schubert and Olson, {James M.} and Cho, {Yoon Jae} and Li, {Xiao Nan} and Crawford, {John R.} and Levy, {Michael L.} and Marcel Kool and Pfister, {Stefan M.} and Taylor, {Michael D.} and Wechsler-Reya, {Robert J.}",

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doi = "10.1016/j.ccell.2016.02.011",

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T1 - HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma

AU - Pei, Yanxin

AU - Liu, Kun Wei

AU - Wang, Jun

AU - Garancher, Alexandra

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.

PY - 2016/3/14

Y1 - 2016/3/14

N2 - 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.

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

Abstract

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