MB-30ONCOLYTIC PICORNAVIRUS SVV-001 PROLONGS ANIMAL SURVIVAL IN A PATIENT TUMOR-DERIVED ORTHOTOPIC XENOGRAFT MOUSE MODEL OF GROUP 3 SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMOR

BACKGROUND: Supratentorial primitive neuroectodermal tumors (sPNET) that express mesenchymal markers (Group 3) often exhibit metastasis at diagnosis and are particularly difficult to treat. Here, we examined the anti-tumor effects of SVV-00, an oncolytic virus that can pass through the blood brain barrier, using our newly established patient tumor-derived orthotopic xenograft mouse model of group 3 sPNET. METHODS: Permissiveness toward SVV-001 was examined in cultured neurospheres and in flow sorted xenograft cells that expressed CD133 and/or CD15, the putative cancer stem cell markers of sPNET. Therapeutic efficacy was determined by systemic treatment of xenograft tumors. Effects of SVV-001 on sPNET metastasis and the mechanism of action were examined through time-course analysis of tumor cell infection, apoptosis and autophagy in vivo. Tumor responsiveness was correlated with the expression of NEUROD1 and ASCL1 mRNA. RESULTS: The cultured sPNET neurospheres as well as the dual- and the mono-positive CD133+ and CD15+ cells were effectively infected by SVV-GFP and killed by SVV-001 (MOI =0.5-25). A single tail vein injection of SVV-001 (9 x 1012 viral particle/kg) significantly prolonged the survival of tumor-bearing mice. In addition to tumor mass, sPNET xenograft cells in CSF spread and local invasion were also effectively killed 72 hr post virus injection. Mechanistically, we found that SVV-001 activated apoptosis and autophagy in vivo. Increased NEUROD1/ASCL1 ratio was found in IC-2664PNT, but no positive correlations were confirmed in medulloblastoma and pediatric high grade gliomas. CONCLUSION: We have identified SVV-001 as a novel agent that can effectively target, at least some of, group 3 sPNET tumor cells, including different subpopulations of cancer stem cells.