A mutant type 2 herpes simplex virus deleted for the protein kinase domain of the ICP10 gene is a potent oncolytic virus

Mol Ther. 2006 May;13(5):882-90. doi: 10.1016/j.ymthe.2006.02.007. Epub 2006 Mar 29.

Abstract

Replication-selective oncolytic herpes simplex virus (HSV) has shown considerable promise as an antitumor agent. Although the current oncolytic HSVs were exclusively constructed from HSV-1, HSV-2 has several unique features that could be exploited to convert the virus to an oncolytic agent. The N-terminus of the HSV-2 ICP10 gene product contains a well-defined serine/threonine protein kinase (PK) domain, which can activate the Ras/MEK/MAPK mitogenic pathway and thus facilitate efficient HSV-2 replication. Because the Ras signaling pathway is a key regulator of normal cell growth and malignant transformation, it is aberrantly activated in many human tumors. Here we report that a mutant HSV-2 (FusOn-H2), constructed by replacing the PK domain of ICP10 with the gene encoding the green fluorescent protein, can selectively replicate in and thus lyse tumor cells. Moreover, infection of FusOn-H2 led to syncytia formation in tumor cells, providing an additional tumor-destroying mechanism. A single moderate-dose injection of FusOn-H2 into established breast cancer xenografts completely eradicated the tumors in more than 80% of the animals, leading to their long-term survival. We conclude that this HSV-2 mutant is a safe and potent oncolytic agent useful for the treatment of malignant solid tumors such as breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Breast Neoplasms / virology*
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Chlorocebus aethiops
  • Female
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hepatocytes / cytology
  • Hepatocytes / virology
  • Herpesvirus 2, Human / genetics*
  • Humans
  • Mice
  • Mice, Nude
  • Models, Genetic
  • Oncolytic Viruses / physiology*
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Ribonucleotide Reductases / chemistry
  • Ribonucleotide Reductases / genetics
  • Ribonucleotide Reductases / physiology*
  • Sequence Deletion*
  • Survival Analysis
  • Vero Cells
  • Virus Replication
  • Xenograft Model Antitumor Assays

Substances

  • Green Fluorescent Proteins
  • ICP10 protein, herpes simplex virus type 2
  • Ribonucleotide Reductases
  • Protein-Serine-Threonine Kinases