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.
authors.affiliation: 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.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Kun-Wei
authors.initials: KW
authors.lastname: Liu
authors.affiliation: Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Garancher
authors.affiliation: Cancer and Immunology Department, Brain Tumor Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Lourdes A
authors.initials: LA
authors.lastname: Esparza
authors.affiliation: Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Maier
authors.affiliation: Department of Pediatrics, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: Yoko T
authors.initials: YT
authors.lastname: Udaka
authors.affiliation: Cancer and Immunology Department, Brain Tumor Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Najiba
authors.initials: N
authors.lastname: Murad
authors.affiliation: Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Sorana
authors.initials: S
authors.lastname: Morrissy
authors.affiliation: Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium, Core Center, 69120 Heidelberg, Germany.
authors.forename: Huriye
authors.initials: H
authors.lastname: Seker-Cin
authors.affiliation: Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium, Core Center, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brabetz
authors.affiliation: Brain Tumor Program, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Qi
authors.affiliation: Brain Tumor Program, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Kogiso
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Schubert
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, Seattle, WA 98109, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Brain Tumor Program, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.affiliation: 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.
authors.forename: John R
authors.initials: JR
authors.lastname: Crawford
authors.affiliation: Department of Neurosurgery, University of California San Diego - Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Levy
authors.affiliation: Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium, Core Center, 69120 Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium, Core Center, 69120 Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: 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.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: 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.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D006655:Histone Deacetylases