title: A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models.
abstract: Difficulties of drug delivery across the blood-brain barrier (BBB) and failure to eliminate cancer stem cells (CSCs) are believed to be the major causes of tumor recurrences in children with medulloblastoma (MB). Seneca Valley virus-001 (SVV-001) is a naturally occurring oncolytic picornavirus that can be systemically administered. Here, we report its antitumor activities against MB cells in a panel of 10 primary tumor-based orthotopic xenograft mouse models. We found that SVV-001 killed the primary cultured xenograft cells, infected and replicated in tumor cells expressing CSC surface marker CD133, and eliminated tumor cells capable of forming neurospheres in vitro in 5 of the 10 xenograft models. We confirmed that SVV-001 could pass through BBB in vivo. A single i.v. injection of SVV-001 in 2 anaplastic MB models led to widespread infection of the preformed intracerebellar (ICb) xenografts, resulting in significant increase in survival (2.2-5.9-fold) in both models and complete elimination of ICb xenografts in 8 of the 10 long-term survivors. Mechanistically, we showed that the intracellular replication of SVV-001 is mediated through a subverted autophagy that is different from the bona fide autophagic process induced by rapamycin. Our data suggest that SVV-001 is well suited for MB treatment. This work expands the current views in the oncolytic therapy field regarding the utility of oncolytic viruses in simultaneous targeting of stem and nonstem tumor cells.
authors.affiliation: Laboratory of Molecular Neuro-oncology, Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin St, MC 3-3320, Houston, TX 77030, USA.
authors.forename: Litian
authors.initials: L
authors.lastname: Yu
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Baxter
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhao
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.forename: Lalita
authors.initials: L
authors.lastname: Wadhwa
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jack M F
authors.initials: JM
authors.lastname: Su
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Tan
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.forename: Adekunle
authors.initials: A
authors.lastname: Adesina
authors.forename: Lazlo
authors.initials: L
authors.lastname: Perlaky
authors.forename: Mary
authors.initials: M
authors.lastname: Hurwitz
authors.forename: Neeraja
authors.initials: N
authors.lastname: Idamakanti
authors.forename: Seshidhar Reddy
authors.initials: SR
authors.lastname: Police
authors.forename: Paul L
authors.initials: PL
authors.lastname: Hallenbeck
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Murali
authors.initials: M
authors.lastname: Chintagumpala
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hurwitz
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier / Q000821:virology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002648:Child; D006801:Humans; D007124:Immunoenzyme Techniques; D007275:Injections, Intravenous; D008527:Medulloblastoma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger