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Targeting Human Medulloblastoma: Oncolytic Virotherapy with Myxoma Virus Is Enhanced by Rapamycin

¹ Departments of Oncology, Clinical Neurosciences, and Biochemistry and Molecular Biology and Tom Baker Cancer Centre; ² Clark H. Smith Integrative Brain Tumour Research Centre, University of Calgary, Calgary, Alberta, Canada; ³ BioTherapeutics Research Group, Robarts Research Institute and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; ⁴ Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida; and ⁵ Ottawa Regional Cancer Centre Research Laboratories, Ottawa, Ontario, Canada

Requests for reprints: Peter A. Forsyth, Tom Baker Cancer Centre, 1331 29 Street Northwest, Calgary, Alberta, Canada T2N 4N2. Phone: 403-210-3934; Fax: 403-210-8135; E-mail: pforsyth{at}ucalgary.ca.

We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model of human glioma. Here, we show that myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. Intratumoral injection of live myxoma virus when compared with control inactivated virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models [D341 median survival: 21 versus 12.5 days; P = 0.0008; Daoy median survival: not reached (three of five mice apparently "cured" after 223 days) versus 75 days; P = 0.0021]. Rapamycin increased the extent of viral oncolysis, "curing" most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice (median survival of mice treated with live virus (LV) and rapamycin, versus LV alone, versus rapamycin alone, versus inactivated virus: 25 days versus 19, 13, and 11 days, respectively; P < 0.0001). Rapamycin increased the levels of constitutively activated Akt in Daoy and D341 cells, which may explain its ability to enhance myxoma virus oncolysis. These observations suggest that myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus. [Cancer Res 2007;67(18):8818–27]

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