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

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165 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
Cell Biology
Cancer Research

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10.1016/j.ccell.2016.02.011

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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.}",

note = "Funding Information: We thank Adriana Charbono and the SBP Animal Facility for assistance with colony maintenance; Amy Cortez and Yoav Altman of the Flow Cytometry Shared Resource and Karl Marquez and Eric O'Connor of the Stem Cell Core at UCSD for help with FACS sorting; Eduard Sergienko, Fu-Yue Zeng, and Thomas Chung of the Conrad Prebys Center for Chemical Genomics for help with assay development and high-throughput screening, and Giovanni Paternostro for help with synergy analysis; Subu Govindarajan of the Analytical Genomics Shared Resource for help with microarray analysis; Feng Qi and Jian-Liang (Jason) Li of the Bioinformatics Shared Resource for help with analysis of microarray data; and Christian Smith for assistance with artwork. This work was supported by NCI grant numbers CA122759 and CA030199 (R.W.R.) and CA159859 (R.W.R. and M.D.T.), by grants from Alex's Lemonade Stand Foundation (R.W.R.) and CureSearch for Children's Cancer (R.W.R. and M.D.T.) and by a Leadership Award ( LA1-01747 ) from the California Institute for Regenerative Medicine (R.W.R.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

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

language = "English (US)",

volume = "29",

pages = "311--323",

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TY - JOUR

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.

N1 - Funding Information: We thank Adriana Charbono and the SBP Animal Facility for assistance with colony maintenance; Amy Cortez and Yoav Altman of the Flow Cytometry Shared Resource and Karl Marquez and Eric O'Connor of the Stem Cell Core at UCSD for help with FACS sorting; Eduard Sergienko, Fu-Yue Zeng, and Thomas Chung of the Conrad Prebys Center for Chemical Genomics for help with assay development and high-throughput screening, and Giovanni Paternostro for help with synergy analysis; Subu Govindarajan of the Analytical Genomics Shared Resource for help with microarray analysis; Feng Qi and Jian-Liang (Jason) Li of the Bioinformatics Shared Resource for help with analysis of microarray data; and Christian Smith for assistance with artwork. This work was supported by NCI grant numbers CA122759 and CA030199 (R.W.R.) and CA159859 (R.W.R. and M.D.T.), by grants from Alex's Lemonade Stand Foundation (R.W.R.) and CureSearch for Children's Cancer (R.W.R. and M.D.T.) and by a Leadership Award ( LA1-01747 ) from the California Institute for Regenerative Medicine (R.W.R.). Publisher Copyright: © 2016 Elsevier Inc.

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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AN - SCOPUS:84962840797

VL - 29

SP - 311

EP - 323

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

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ER -

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

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