1. ¹Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
2. ²Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
3. ³Physician Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
4. ⁴Graduate Program of Molecular and Developmental Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
5. ⁵Department of Pediatric General, Thoracic, and Fetal Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
6. ⁶Division of Biochemistry and Molecular Biology, Institute for Genetic Medicine, University of Southern California, Los Angeles, California, USA
7. ⁷Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

Correspondence: Timothy P Cripe, Division of Hematology/Oncology ML7015, 3333 Burnet Ave, Cincinnati, Ohio 45229, USA. E-mail: timothy.cripe@cchmc.org

Received 8 January 2006; Accepted 25 August 2006.

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs), driven in part by hyperactive Ras and epidermal growth factor receptor (EGFR) signaling, are often incurable. Testing of therapeutics for MPNST has been hampered by lack of adequate xenograft models. We previously documented that human MPNST cells are permissive for lytic infection by oncolytic herpes simplex viruses (oHSV). Herein we developed and characterized a xenograft model of human MPNST and evaluated the antitumor effects of oHSV mutants (G207 and hrR3) and the EGFR inhibitor, erlotinib. Additive cytotoxicity of these agents was found in human MPNST cell lines, suggesting that EGFR signaling is not critical for virus replication. Mice bearing human MPNST tumors treated with G207 or hrR3 by intraperitoneal or intratumoral injection showed tumor-selective virus biodistribution, virus replication, and reduced tumor burden. oHSV injection demonstrated more dramatic antitumor activity than erlotinib. Combination therapies showed a trend toward an increased antiproliferative effect. Both oHSV and erlotinib were antiangiogenic as measured by proangiogenic gene expression, effect on endothelial cells and xenograft vessel density. Overall, oHSVs showed highly potent antitumor effects against MPNST xenografts, an effect not diminished by EGFR inhibition. Our data suggest that inclusion of MPNSTs in clinical trials of oHSV is warranted.