TY - JOUR
T1 - Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression
AU - Friedman, Gregory K.
AU - Bernstock, Joshua D.
AU - Chen, Dongquan
AU - Nan, Li
AU - Moore, Blake P.
AU - Kelly, Virginia M.
AU - Youngblood, Samantha L.
AU - Langford, Catherine P.
AU - Han, Xiaosi
AU - Ring, Eric K.
AU - Beierle, Elizabeth A.
AU - Gillespie, G. Yancey
AU - Markert, James M.
N1 - Funding Information:
We thank the Analytic and Preparative Core Facility (supported by P30 AR048311 and P30 AI027767) for assistance with flow cytometry analysis; Michael Crowley, Ph.D., and the Heflin Center for Genomic Science (supported by CA13148-40) for assistance with STR profiling. Supported in part by grants from the St. Baldrick’s Foundation, the Rally Foundation for Childhood Cancer Research, the Truth 365, Hyundai Hope on Wheels, the Department of Defense (W81XWH-15-1-0108) and the Food and Drug Administration Office of Orphan Products Development (R01FD005379) to GKF, the American Brain Tumor Association (MSSF1800013) to JDB and from the National Institutes of Health (P20CA151129 to GYG and P01CA071933 to JMM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Defense.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Pediatric high-grade brain tumors and adult glioblastoma are associated with significant morbidity and mortality. Oncolytic herpes simplex virus-1 (oHSV) is a promising approach to target brain tumors; oHSV G207 and M032 (encodes human interleukin-12) are currently in phase I clinical trials in children with malignant supratentorial brain tumors and adults with glioblastoma, respectively. We sought to compare the sensitivity of patient-derived pediatric malignant brain tumor and adult glioblastoma xenografts to these clinically-relevant oHSV. In so doing we found that pediatric brain tumors were more sensitive to the viruses and expressed significantly more nectin-1 (CD111) than adult glioblastoma. Pediatric embryonal and glial tumors were 74-fold and 14-fold more sensitive to M002 and 16-fold and 6-fold more sensitive to G207 than adult glioblastoma, respectively. Of note, pediatric embryonal tumors were more sensitive than glial tumors. Differences in sensitivity may be due in part to nectin-1 expression, which predicted responses to the viruses. Treatment with oHSV resulted in prolonged survival in both pediatric and adult intracranial patient-dervied tumor xenograft models. Our results suggest that pediatric brain tumors are ideal targets for oHSV and that brain tumor expression of nectin-1 may be a useful biomarker to predict patient response to oHSV.
AB - Pediatric high-grade brain tumors and adult glioblastoma are associated with significant morbidity and mortality. Oncolytic herpes simplex virus-1 (oHSV) is a promising approach to target brain tumors; oHSV G207 and M032 (encodes human interleukin-12) are currently in phase I clinical trials in children with malignant supratentorial brain tumors and adults with glioblastoma, respectively. We sought to compare the sensitivity of patient-derived pediatric malignant brain tumor and adult glioblastoma xenografts to these clinically-relevant oHSV. In so doing we found that pediatric brain tumors were more sensitive to the viruses and expressed significantly more nectin-1 (CD111) than adult glioblastoma. Pediatric embryonal and glial tumors were 74-fold and 14-fold more sensitive to M002 and 16-fold and 6-fold more sensitive to G207 than adult glioblastoma, respectively. Of note, pediatric embryonal tumors were more sensitive than glial tumors. Differences in sensitivity may be due in part to nectin-1 expression, which predicted responses to the viruses. Treatment with oHSV resulted in prolonged survival in both pediatric and adult intracranial patient-dervied tumor xenograft models. Our results suggest that pediatric brain tumors are ideal targets for oHSV and that brain tumor expression of nectin-1 may be a useful biomarker to predict patient response to oHSV.
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U2 - 10.1038/s41598-018-32353-x
DO - 10.1038/s41598-018-32353-x
M3 - Article
C2 - 30224769
AN - SCOPUS:85053483614
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 13930
ER -
