title: In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells.
abstract: BACKGROUND
  Brain tumor-initiating cells (BTICs) are stem-like cells hypothesized to form a disease reservoir that mediates tumor recurrence in high-grade gliomas. Oncolytic virotherapy uses replication-competent viruses to target and kill malignant cells and has been evaluated in clinic for glioma therapy with limited results. Myxoma virus (MyxV) is a safe and highly effective oncolytic virus (OV) in conventional glioma models but, as seen with other OVs, is only modestly effective for patient-derived BTICs. The objective of this study was to determine whether MyxV treatment against human BTICs could be improved by combining chemotherapeutics and virotherapy.
  
  
  METHODS
  A 73-compound library of drug candidates in clinical use or preclinical development was screened to identify compounds that sensitize human BTICs to MyxV treatment in vitro, and synergy was evaluated mathematically in lead compounds using Chou-Talalay analyses. The effects of combination therapy on viral gene expression and viral replication were also assessed.
  
  
  RESULTS
  Eleven compounds that enhance MyxV efficacy were identified, and 6 were shown to synergize with the virus using Chou-Talalay analyses. Four of the synergistic compounds were shown to significantly increase viral gene expression, indicating a potential mechanism for synergy. Three highly synergistic compounds (axitinib, a VEGFR inhibitor; rofecoxib, a cyclooxygenase-2 inhibitor; and pemetrexed, a folate anti-metabolite) belong to classes of compounds that have not been previously shown to synergize with oncolytic viruses in vitro.
  
  
  CONCLUSIONS
  This study has identified multiple novel drug candidates that synergistically improve MyxV efficacy in a preclinical BTIC glioma model.
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Brienne A
authors.initials: BA
authors.lastname: McKenzie
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Zemp
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pisklakova
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Rajappa S
authors.initials: RS
authors.lastname: Kenchappa
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Ebba U
authors.initials: EU
authors.lastname: Kurz
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Canada (B.A.M., F.J.Z., A.N., X.L, E.U.K, P.A.F.); Department of Pediatrics, University of Calgary, Calgary, Canada (A.N.); Department of Oncology, University of Calgary, Calgary, Canada (A.N., P.A.F.); Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada (E.U.K.); Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K, P.A.F.); Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida (G.M.).
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000077784:Axitinib; D001932:Brain Neoplasms / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005909:Glioblastoma / Q000628:therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D066298:In Vitro Techniques; D007191:Indazoles / Q000008:administration & dosage / Q000627:therapeutic use; D009233:Myxoma virus / Q000235:genetics / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000821:virology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D054852:Small Molecule Libraries; D000077784:Axitinib
keywords: brain tumor-initiating cells; myxoma virus; oncolytic virotherapy; synergy