Reovirus prolongs survival and reduces the frequency of spinal and leptomeningeal metastases from medulloblastoma.
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.
Yang
Wen Qing
WQ
Department of Oncology, University of Calgary and Tom Baker Cancer Centre, Calgary, Alberta, T2N 4N2 Canada.
Senger
Donna
D
Muzik
Huong
H
Shi
Zhong Qiao
ZQ
Johnson
Denise
D
Brasher
Penny M A
PM
Rewcastle
N Barry
NB
Hamilton
Mark
M
Rutka
Jim
J
Wolff
Johannes
J
Wetmore
Cynthia
C
Curran
Tom
T
Lee
Patrick W K
PW
Forsyth
Peter A
PA
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
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)