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

Cancer Cell. 2016 Mar 14;29(3):311-323. doi: 10.1016/j.ccell.2016.02.011.

Authors

Yanxin Pei¹, Kun-Wei Liu², Jun Wang², Alexandra Garancher², Ran Tao³, Lourdes A Esparza², Donna L Maier², Yoko T Udaka⁴, Najiba Murad³, Sorana Morrissy⁵, Huriye Seker-Cin⁶, Sebastian Brabetz⁶, Lin Qi⁷, Mari Kogiso⁷, Simone Schubert⁸, James M Olson⁹, Yoon-Jae Cho⁸, Xiao-Nan Li⁷, John R Crawford¹⁰, Michael L Levy¹¹, Marcel Kool⁶, Stefan M Pfister⁶, Michael D Taylor¹², Robert J Wechsler-Reya¹³

Affiliations

¹ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Cancer and Immunology Department, Brain Tumor Institute, Children's National Medical Center, Washington, DC 20010, USA.
² Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
³ Cancer and Immunology Department, Brain Tumor Institute, Children's National Medical Center, Washington, DC 20010, USA.
⁴ Department of Pediatrics, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA.
⁵ Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁶ Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium, Core Center, 69120 Heidelberg, Germany.
⁷ Brain Tumor Program, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁸ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, Seattle, WA 98109, USA.
¹⁰ Department of Pediatrics, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA; Department of Neurosciences, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA.
¹¹ Department of Neurosurgery, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA.
¹² Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹³ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: rwreya@sbpdiscovery.org.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation / drug effects*
Disease Models, Animal
Forkhead Transcription Factors / metabolism
Genes, Tumor Suppressor / drug effects
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Medulloblastoma / drug therapy*
Medulloblastoma / metabolism*
Mice
Mice, Inbred C57BL
Phosphoinositide-3 Kinase Inhibitors*
Proto-Oncogene Proteins c-myc / metabolism*

Substances

Forkhead Transcription Factors
Histone Deacetylase Inhibitors
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding