Systemic Delivery of γ134.5-Deleted Herpes Simplex Virus-1 Selectively Targets and Treats Distant Human Xenograft Tumors That Express High MEK Activity

Abstract

Abstract#; 1 34.5 mutant herpes simplex type 1 viruses are under active clinical investigation as oncolytic therapy for cancer. Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) activity has been shown to suppress protein kinase R and thereby confer oncolytic susceptibility to some human tumors by R3616, a virus deleted for both copies of g 1 34.5. We report that systemic delivery of R3616 can selectively target and destroy human xenograft tumors that overexpress MEK activity compared with tumors that express lower MEK activity. These results suggest systemic delivery of R3616 may be effective in the treatment of some human tumors. [Cancer Res 2007;67(17):8301-6]

Gene therapy progress and prospects cancer: oncolytic viruses

“…Apart from the Akt pathway targeted by myxoma virus described above, HSV g34.5-deleted mutants showed enhanced replication in cells with activated mitogen-activated protein (MAP) kinase or extracellular signal-regulated (ERK) kinase, which in turn inhibited protein kinase R activity, thus circumventing the negative impact of the IFN signaling pathway. 40,41 Similarly, viruses such as VSV showed preferential replication in cells with an activated Ras-ERK pathway and defective IFN pathways. 42 A vaccinia virus mutant with a deletion in B18R, whose gene product neutralizes type I IFNs, showed IFN-dependent cancer selectivity and efficacy.…”

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

“…In Us3 -herpesvirus-infected tumor cells, the PI3K-Akt pathway is active and is susceptible to inhibition by LY294002 [236,237]. Herpesvirus R3616 lacks both copies of its γ 1 34.5 neurovirulence genes [426]. Human tumor cells frequently overexpress the mitogen-activated protein kinase and extracellular signal-regulated kinase kinase pathways, which suppress protein kinase R, and create an IFN-free environment.…”

“…The oncolytic R3616 herpesvirus readily replicates in such human tumor cells J. G. Sinkovics and J. C. Horvath: Viral agents in treatment cancers 36s immunoevasive genes and gene product proteins inhibiting expression of major histocompatibilty complex (MHC) class I molecules in infected cells, protecting infected cells against apoptosis, counteracting the the dsRNA-responsive eIF2α kinase, protein kinase R, and inhibiting 2'-5' oligoadenylate synthetase in infected cells, thus creating an interferon-free intracellular environment, eIF2α -eukaryotic initiation factor α subunit. and in their metastases [426]. Innate immunity, especially microglia activation in the brain, eliminates oncolytic viruses injected directly into brain tumors.…”

Anticancer Gene Transfer for Cancer Gene Therapy

“…The latter is a host defense pathway, which halts protein synthesis of virally-infected cells and induces their death. Since activated Ras leads to inactivation of PKR, oncolytics like HSV-1 or Influenza virus A (IFA) are able to conditionally replicate only in cancer cells using this common defect of protein synthesis inhibition in tumors (Smith et al, 2006;Veerapong et al, 2007;Bergmann et al, 2001;Muster et al, 2004). Ras pathway has a central role in tumor initiation, progression and sensitivity to treatment.…”