title: A novel oncolytic herpes simplex virus that synergizes with phosphoinositide 3-kinase/Akt pathway inhibitors to target glioblastoma stem cells.
abstract: OBJECTIVE
  To develop a new oncolytic herpes simplex virus (oHSV) for glioblastoma (GBM) therapy that will be effective in glioblastoma stem cells (GSC), an important and untargeted component of GBM. One approach to enhance oHSV efficacy is by combination with other therapeutic modalities.
  
  
  METHODS
  MG18L, containing a U(S)3 deletion and an inactivating LacZ insertion in U(L)39, was constructed for the treatment of brain tumors. Safety was evaluated after intracerebral injection in HSV-susceptible mice. The efficacy of MG18L in human GSCs and glioma cell lines in vitro was compared with other oHSVs, alone or in combination with phosphoinositide-3-kinase (PI3K)/Akt inhibitors (LY294002, triciribine, GDC-0941, and BEZ235). Cytotoxic interactions between MG18L and PI3K/Akt inhibitors were determined using Chou-Talalay analysis. In vivo efficacy studies were conducted using a clinically relevant mouse model of GSC-derived GBM.
  
  
  RESULTS
  MG18L was severely neuroattenuated in mice, replicated well in GSCs, and had anti-GBM activity in vivo. PI3K/Akt inhibitors displayed significant but variable antiproliferative activities in GSCs, whereas their combination with MG18L synergized in killing GSCs and glioma cell lines, but not human astrocytes, through enhanced induction of apoptosis. Importantly, synergy was independent of inhibitor sensitivity. In vivo, the combination of MG18L and LY294002 significantly prolonged survival of mice, as compared with either agent alone, achieving 50% long-term survival in GBM-bearing mice.
  
  
  CONCLUSIONS
  This study establishes a novel therapeutic strategy: oHSV manipulation of critical oncogenic pathways to sensitize cancer cells to molecularly targeted drugs. MG18L is a promising agent for the treatment of GBM, being especially effective when combined with PI3K/Akt pathway-targeted agents.
authors.affiliation: Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kanai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rabkin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000628:therapy / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D008805:Mice, Inbred A; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D018139:Simplexvirus / Q000235:genetics* / Q000502:physiology; D014779:Virus Replication / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt