title: DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets.
abstract: We used human stem and progenitor cells to develop a genetically accurate novel model of MYC-driven Group 3 medulloblastoma. We also developed a new informatics method, Disease-model Signature versus Compound-Variety Enriched Response ("DiSCoVER"), to identify novel therapeutics that target this specific disease subtype.
  
  
  
  Human neural stem and progenitor cells derived from the cerebellar anlage were transduced with oncogenic elements associated with aggressive medulloblastoma. An in silico analysis method for screening drug sensitivity databases (DiSCoVER) was used in multiple drug sensitivity datasets. We validated the top hits from this analysis in vitro and in vivo
  
  
  
  Human neural stem and progenitor cells transformed with c-MYC, dominant-negative p53, constitutively active AKT and hTERT formed tumors in mice that recapitulated Group 3 medulloblastoma in terms of pathology and expression profile. DiSCoVER analysis predicted that aggressive MYC-driven Group 3 medulloblastoma would be sensitive to cyclin-dependent kinase (CDK) inhibitors. The CDK 4/6 inhibitor palbociclib decreased proliferation, increased apoptosis, and significantly extended the survival of mice with orthotopic medulloblastoma xenografts.
  
  
  
  We present a new method to generate genetically accurate models of rare tumors, and a companion computational methodology to find therapeutic interventions that target them. We validated our human neural stem cell model of MYC-driven Group 3 medulloblastoma and showed that CDK 4/6 inhibitors are active against this subgroup. Our results suggest that palbociclib is a potential effective treatment for poor prognosis MYC-driven Group 3 medulloblastoma tumors in carefully selected patients. Clin Cancer Res; 22(15); 3903-14. ©2016 AACR.
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Hanaford
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Cambridge, Massachusetts.
authors.forename: Tenley C
authors.initials: TC
authors.lastname: Archer
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Price
authors.affiliation: Department of Neurosurgery, Heinrich-Heine University Hospital, Duesseldorf, Germany.
authors.forename: Ulf D
authors.initials: UD
authors.lastname: Kahlert
authors.affiliation: Department of Neurosurgery, Heinrich-Heine University Hospital, Duesseldorf, Germany.
authors.forename: Jarek
authors.initials: J
authors.lastname: Maciaczyk
authors.affiliation: Department of Neurosurgery, University Hospital, Stuttgart, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Nikkhah
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ehrenberger
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Vlado
authors.initials: V
authors.lastname: Dančík
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Brinton
authors.initials: B
authors.lastname: Seashore-Ludlow
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Viswanathan
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Stewart
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rees
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Alykhan
authors.initials: A
authors.lastname: Shamji
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Stuart
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Ernest
authors.initials: E
authors.lastname: Fraenkel
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Cambridge, Massachusetts.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Medicine, University of California San Diego, La Jolla, California. Moores Cancer Center, University of California San Diego, La Jolla, California.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.affiliation: Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Medicine, University of California San Diego, La Jolla, California. Moores Cancer Center, University of California San Diego, La Jolla, California.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland. eraabe2@jhmi.edu ceberha@jhmi.edu.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland. Division of Pediatric Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland. eraabe2@jhmi.edu ceberha@jhmi.edu.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Raabe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000235:genetics*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D055808:Drug Discovery; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D058953:Neural Stem Cells / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; C500026:palbociclib