Meduloblastoma

Neuro-Oncology 12(10):1034 – 1042, 2010. doi:10.1093/neuonc/noq057 Advance Access publication May 21, 2010

N E U RO - O N CO LO GY

Treatment of medulloblastoma with a modified measles virus
Adam W. Studebaker, Cole R. Kreofsky, Christopher R. Pierson, Stephen J. Russell, Evanthia Galanis, and Corey Raffel
The Center for Childhood Cancer, The Research Institute at Nationwide Children’sHospital, Department of Pediatrics, The Ohio State University, Columbus, Ohio (A.W.S., C.R.P.); Wayne State University School of Medicine, Detroit, Michigan (C.R.K.); Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (S.J.R.); Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota (E.G.); Department of Neurological Surgery, The Ohio State University College of Medicine,Columbus, Ohio (C.R.)

Although treatment of medulloblastoma has improved, at least 30% of patients with this tumor die of progressive disease. Unfortunately, many of the children who survive suffer long-term treatment-related morbidity. Previous studies have demonstrated the efficacy of using oncolytic viruses to eradicate brain tumors. The objective of this study was to test the efficacy of measlesvirus in treating medulloblastoma. To determine whether medulloblastoma cells are susceptible, 5 different human medulloblastoma cell lines were analyzed for the expression of the measles virus receptor CD46. Fluorescence-activated cell-sorting analysis confirmed expression of CD46 on all cell lines tested, with UW288-1 having the most prominent expression and D283med displaying the lowestexpression. CD46 expression was also demonstrated, using immunohistochemistry, in 13 of 13 medulloblastoma tissue specimens. All 5 medulloblastoma cell lines were examined for their susceptibility to measles virus killing in vitro. A measles virus containing the green fluorescent protein (GFP) gene as a marker for infection (MVGFP) was used. All cell lines exhibited significant killing when infected withMV-GFP, all formed syncytia with infection, all showed fluorescence, and all allowed viral replicaton after infection. In an intracerebral murine xenograft model, a statistically significant increase in survival was seen in animals treated with the active measles virus compared with those treated with inactivated virus. These data demonstrate that medulloblastoma is susceptible to measles viruskilling

and that the virus may have a role in treating this tumor in the clinical setting. Keywords: bioluminescence, measles virus, medulloblastoma, oncolytic virus.

Received February 22, 2010; accepted April 16, 2010. Corresponding Author: Corey Raffel, MD, PhD, Department of Neurological Surgery, The Ohio State University, Columbus, Ohio 43210 (corey.raffel@nationwidechildrens.org).

raintumors are the most common solid tumors of childhood, occurring at a rate of 2– 5 cases per 100 000 annually.1 Medulloblastoma accounts for 20% of these tumors.2 Traditionally, medulloblastomas have been treated with radical surgical resection and radiation therapy, resulting in 5-year survival rates of about 60%.3,4 As the devastating effects of radiation therapy to the pediatric brain have beenrecognized, emphasis has been placed on decreasing the dose of radiation used and adding systemic chemotherapy.5 Although these refinements in treatment have increased the 5-year survival to close to 70%,6 there still is significant mortality and morbidity associated with the treatment. Thus, there is an urgent need to investigate alternative therapeutic approaches that are more effective and have lesstoxic side effects. Measles virus, a negative strand RNA virus, kills cells by inducing the formation of multinuclear cell aggregates known as syncytia, which result from the fusion of infected cells.7 The virus enters the cell by binding of its H glycoprotein to the membrane-bound cell receptor’s signaling lymphocyte activation molecule (SLAM), found predominately on lymphocytes, or CD46,...