title: Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.
abstract: We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased survival of mice bearing cortical implants of mouse and human G3 MBs that overexpress MYC compared to each agent alone, while having little effect on mouse MBs of the sonic hedgehog subgroup. Our findings strongly suggest that combination therapy with pemetrexed and gemcitabine is a promising treatment for G3 MBs.
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Morfouace
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Anang
authors.initials: A
authors.lastname: Shelat
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Jacus
authors.affiliation: Department of Preclinical Pharmacokinetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Burgess B
authors.initials: BB
authors.lastname: Freeman
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Turner
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Robinson
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Frederique
authors.initials: F
authors.lastname: Zindy
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Wang
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Institut Curie/CNRS UMR 3306/INSERM U1005 Building 110, Centre Universitaire, 91405 Orsay, Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Ayrault
authors.affiliation: Institut Curie/CNRS UMR 3306/INSERM U1005 Building 110, Centre Universitaire, 91405 Orsay, Cedex, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Bihannic
authors.affiliation: AP-HP, Department of Neurosurgery, Necker-Enfants Malades Hospital, Université Rene Descartes, 75015 Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Puget
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.affiliation: Department of Pediatric Hematology-Oncology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.affiliation: Department of NeuroOncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Giles W
authors.initials: GW
authors.lastname: Robinson
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.affiliation: Department of NeuroOncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: martine.roussel@stjude.org.
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D057166:High-Throughput Screening Assays; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D000068437:Pemetrexed; D011379:Prognosis; D000093542:Gemcitabine
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D000093542:Gemcitabine