title: Treating brain tumor-initiating cells using a combination of myxoma virus and rapamycin.
abstract: BACKGROUND
  Intratumoral heterogeneity in glioblastoma multiforme (GBM) poses a significant barrier to therapy in certain subpopulation such as the tumor-initiating cell population, being shown to be refractory to conventional therapies. Oncolytic virotherapy has the potential to target multiple compartments within the tumor and thus circumvent some of the barriers facing conventional therapies. In this study, we investigate the oncolytic potential of myxoma virus (MYXV) alone and in combination with rapamycin in vitro and in vivo using human brain tumor-initiating cells (BTICs).
  
  
  METHODS
  We cultured fresh GBM specimens as neurospheres and assayed their growth characteristics in vivo. We then tested the susceptibility of BTICs to MYXV infection with or without rapamycin in vitro and assessed viral biodistribution/survival in vivo in orthotopic xenografts.
  
  
  RESULTS
  The cultured neurospheres were found to retain stem cell markers in vivo, and they closely resembled human infiltrative GBM. In this study we determined that (i) all patient-derived BTICs tested, including those resistant to temozolomide, were susceptible to MYXV replication and killing in vitro; (ii) MYXV replicated within BTICs in vivo, and intratumoral administration of MYXV significantly prolonged survival of BTIC-bearing mice; (iii) combination therapy with MYXV and rapamycin improved antitumor activity, even in mice bearing "advanced" BTIC tumors; (iv) MYXV treatment decreased expression of stem cell markers in vitro and in vivo.
  
  
  CONCLUSIONS
  Our study suggests that MYXV in combination with rapamycin infects and kills both the BTICs and the differentiated compartments of GBM and may be an effective treatment even in TMZ-resistant patients.
authors.affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Southern Alberta Cancer Research Institute, Calgary, Canada.
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Zemp
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.forename: Brienne A
authors.initials: BA
authors.lastname: McKenzie
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Zhou
authors.forename: Lori
authors.initials: L
authors.lastname: Maxwell
authors.forename: Beichen
authors.initials: B
authors.lastname: Sun
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kelly
authors.forename: Owen
authors.initials: O
authors.lastname: Stechishin
authors.forename: Artee
authors.initials: A
authors.lastname: Luchman
authors.forename: Samuel
authors.initials: S
authors.lastname: Weiss
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Cairncross
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hamilton
authors.forename: Brian A
authors.initials: BA
authors.lastname: Rabinovich
authors.forename: Masmudur M
authors.initials: MM
authors.lastname: Rahman
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Mohamed
authors.forename: Sherin
authors.initials: S
authors.lastname: Smallwood
authors.forename: Donna L
authors.initials: DL
authors.lastname: Senger
authors.forename: John
authors.initials: J
authors.lastname: Bell
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000517:prevention & control* / Q000556:secondary / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009233:Myxoma virus / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000821:virology; D050130:Oncolytic Virotherapy; D011213:Poxviridae Infections / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D020123:Sirolimus / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D008156:Luciferases; D020123:Sirolimus
keywords: brain tumor initiating cells; malignant glioma; myxoma virus; oncolytic virus; rapamycin