Malignant peripheral nerve sheath tumors with high and low Ras-GTP are permissive for oncolytic herpes simplex virus mutants

Abstract

Background: Malignant peripheral nerve sheath tumors (MPNSTs) occur most frequently in patients with neurofibromatosis type 1 and are often fatal. Current therapy relies upon radical surgical resection, which often fails to completely remove the tumor. To address the need for novel treatment approaches for this disease, we sought to determine if human MPNST-derived cell lines are sensitive to oncolytic Herpes simplex virus (oHSV) infection. Activation of the Ras pathway and its inhibitory effects on protein kinase R (PKR) activation have been shown to dictate cellular permissivity to oHSV mutants. Because NF-1-associated MPNSTs possess inherent hyperactive Ras, we hypothesized these tumors would be ideal therapeutic targets for oHSVs.

Procedure: Human MPNST-derived cell lines were examined for sensitivity to oHSV-mediated gene transduction, virus replication, cytotoxicity, and apoptosis. These parameters were correlated with PKR activation following oHSV infection and compared with normal human Schwann cells (NHSCs) without hyperactive Ras.

Results: MPNST-derived cell lines were efficiently transduced, supported virus replication and were killed by the oncolytic HSV mutants, including sporadic MPNSTs without hyperactive Ras. In contrast to the highly sensitive MPNST cell lines, NHSCs did not support mutant virus replication.

Conclusions: MPNSTs are susceptible to lysis by oncolytic HSV mutants, regardless of Ras status. Tumor-selective virus replication in MPNST cells appears to be mediated by both cellular expression of ribonucleotide reductase and prevention of eIF2alpha phosphorylation. Virus-induced cytotoxicity of MPNST cell lines was caused by both direct lysis and apoptosis. Our data suggest the use of oncolytic HSV mutants may represent a novel treatment approach for patients with MPNSTs.