title: Reovirus prolongs survival and reduces the frequency of spinal and leptomeningeal metastases from medulloblastoma.
abstract: Medulloblastoma (MB), the most common pediatric brain tumor, is a highly malignant disease with a 5-year survival rate of only 60%. Tumor cells invade surrounding tissue and disseminate through cerebral spinal fluid, making treatment difficult. Human reovirus type 3 exploits an activated Ras pathway in tumor cells to support productive infection as an oncolytic virus. Here, we examined the ability of human reovirus to kill MB cells lines and surgical specimens in vitro and inhibit tumor growth/metastases in vivo. Most human MB cell lines tested (five of seven = 71.4%), two MB cell lines derived from spontaneously arising tumors in Patched-1(+/-) mice (two of two = 100%) and three MB primary cultures derived from surgical specimens, were susceptible to reovirus infection. Reovirus was internalized and transcribed in both susceptible and resistant cell lines. However, viral protein synthesis was restricted to cell lines with higher levels of activated Ras, suggesting that Ras plays a critical role in reovirus oncolysis in MB. Using an in vivo Daoy orthotopic animal model, we found that a single i.t. injection of reovirus dramatically prolonged survival compared with controls (160 versus 70 days, respectively; P = 0.0003). Repeating this experiment with GFP-labeled Daoy cells and multiple i.t. administrations of reovirus, we again found prolonged survival and a dramatic reduction in spinal and leptomeningeal metastases (66.7% in control injections versus 0.0% in the live virus group). These data suggest that this oncolytic virus may be a potentially effective novel therapy against human MB. Its ability to reduce metastases to the spinal cord could allow a reduction in the dose/field of total neuroaxis cerebral-spinal radiotherapy currently used to treat/prevent cerebral spinal fluid dissemination.
authors.affiliation: Department of Oncology, University of Calgary and Tom Baker Cancer Centre, Calgary, Alberta, T2N 4N2 Canada.
authors.forename: Wen Qing
authors.initials: WQ
authors.lastname: Yang
authors.forename: Donna
authors.initials: D
authors.lastname: Senger
authors.forename: Huong
authors.initials: H
authors.lastname: Muzik
authors.forename: Zhong Qiao
authors.initials: ZQ
authors.lastname: Shi
authors.forename: Denise
authors.initials: D
authors.lastname: Johnson
authors.forename: Penny M A
authors.initials: PM
authors.lastname: Brasher
authors.forename: N Barry
authors.initials: NB
authors.lastname: Rewcastle
authors.forename: Mark
authors.initials: M
authors.lastname: Hamilton
authors.forename: Jim
authors.initials: J
authors.lastname: Rutka
authors.forename: Johannes
authors.initials: J
authors.lastname: Wolff
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wetmore
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
mesh_terms: D000818:Animals; D001691:Biological Therapy; D002528:Cerebellar Neoplasms / Q000628:therapy*; D004334:Drug Administration Schedule; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors; D005260:Female; D017930:Genes, Reporter; D016158:Genes, p53; D049452:Green Fluorescent Proteins; D006801:Humans; D007278:Injections, Spinal; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D012089:Mammalian orthoreovirus 3 / Q000502:physiology*; D008527:Medulloblastoma / Q000517:prevention & control / Q000556:secondary* / Q000628:therapy; D008577:Meningeal Neoplasms / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D015398:Signal Transduction; D013120:Spinal Cord Neoplasms / Q000517:prevention & control / Q000556:secondary*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D015852:Eukaryotic Initiation Factor-2; D008164:Luminescent Proteins; D009363:Neoplasm Proteins; D049452:Green Fluorescent Proteins; D019892:eIF-2 Kinase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)