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Abstract
Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA)-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA) enhanced rRp450’s in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors.
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1 Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
2 Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA; Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Division of Anatomy, The Ohio State University, Columbus, OH 43210, USA
3 Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children’s Hospital, Columbus, OH 43205, USA
4 Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21287, USA
5 Department of Neurosurgery, Nationwide Children’s Hospital, Columbus, OH 43205, USA