title: Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma.
abstract: Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate our findings we used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC. Our results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, we provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma.
authors.affiliation: Division of Neurosurgery, Department of Surgery, The Hospital for Sick Children, Toronto, Canada.|Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.|Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Faria
authors.affiliation: Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.affiliation: Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Golbourn
authors.affiliation: Division of Neurosurgery, Department of Surgery, The Hospital for Sick Children, Toronto, Canada.|Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Roberto J
authors.initials: RJ
authors.lastname: Diaz
authors.affiliation: Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Olsen
authors.affiliation: Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bryant
authors.affiliation: Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bebenek
authors.affiliation: Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: Bertrand
authors.affiliation: Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kushida
authors.affiliation: Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Renee
authors.initials: R
authors.lastname: Head
authors.affiliation: Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Clark
authors.affiliation: Division of Neurosurgery, Department of Surgery, The Hospital for Sick Children, Toronto, Canada.|Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Dirks
authors.affiliation: Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Smith
authors.affiliation: Division of Neurosurgery, Department of Surgery, The Hospital for Sick Children, Toronto, Canada.|Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Division of Neurosurgery, Department of Surgery, The Hospital for Sick Children, Toronto, Canada.|Program in Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
mesh_terms: D000098:Acetophenones / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D001552:Benzazepines / Q000737:chemistry*; D001578:Benzopyrans / Q000737:chemistry; D001932:Brain Neoplasms / Q000188:drug therapy; D002460:Cell Line; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004148:Dioxolanes / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005444:Flunarizine / Q000737:chemistry; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D010881:Piperidones
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D001552:Benzazepines; D001578:Benzopyrans; D018844:Cyclin-Dependent Kinases; D004148:Dioxolanes; D005444:Flunarizine; D007211:Indoles; D016271:Proto-Oncogene Proteins c-myc; D012313:RNA; C489427:MYC protein, human; C120793:alsterpaullone; C085746:rottlerin; C498077:piperlongumine; D010881:Piperidones
keywords: alsterpaullone; connectivity map; group 3 medulloblastoma; piperlongumine