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Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models
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Malignant peripheral nerve sheath tumors with high and low Ras-GTP are permissive for oncolytic herpes simplex virus

Yonatan Y Mahller1, Fatima Rangwala, Nancy Ratner

  • 1Division of Hematology/Oncology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.

Pediatric Blood & Cancer
|August 27, 2005
PubMed
Abstract

Insights

Oncolytic Herpes simplex virus (oHSV) mutants effectively kill malignant peripheral nerve sheath tumors (MPNSTs) by selective replication and inducing cell death. This suggests oHSV as a promising new therapy for MPNSTs.

Area of Science:

  • Oncology
  • Virology
  • Genetics

Background:

  • Malignant peripheral nerve sheath tumors (MPNSTs), often linked to neurofibromatosis type 1, are aggressive and difficult to treat with surgery alone.
  • Current therapeutic strategies for MPNSTs are limited, necessitating the development of novel treatment modalities.
  • The Ras pathway's role in regulating cellular permissivity to oncolytic Herpes simplex virus (oHSV) mutants is known, with hyperactive Ras in NF-1-associated MPNSTs suggesting potential therapeutic vulnerability.

Purpose of the Study:

  • To investigate the sensitivity of human MPNST-derived cell lines to oncolytic Herpes simplex virus (oHSV) infection.
  • To determine if oHSV can effectively target and induce cell death in MPNSTs, irrespective of Ras pathway activation.
  • To explore the mechanisms underlying oHSV's efficacy in MPNSTs, including viral replication, cytotoxicity, and apoptosis.

Main Methods:

  • Human MPNST cell lines and normal human Schwann cells (NHSCs) were infected with oHSV mutants.
  • Sensitivity was assessed by measuring oHSV-mediated gene transduction, viral replication, cytotoxicity, and apoptosis.
  • Results were correlated with Protein Kinase R (PKR) activation status post-infection.

Main Results:

  • MPNST-derived cell lines demonstrated efficient transduction and supported oHSV replication, leading to significant cell killing.
  • oHSV mutants effectively lysed MPNST cells, including those without hyperactive Ras.
  • Normal human Schwann cells (NHSCs) did not support mutant oHSV replication, indicating tumor selectivity.

Conclusions:

  • MPNSTs are highly susceptible to lysis by oncolytic HSV mutants, irrespective of their Ras pathway activation status.
  • Tumor-selective oHSV replication in MPNSTs involves cellular ribonucleotide reductase expression and prevention of eIF2alpha phosphorylation.
  • oHSV-induced cytotoxicity in MPNSTs occurs through direct lysis and apoptosis, supporting its potential as a novel therapeutic strategy.

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