Oncotarget

Research Papers:

Tumour-specific triple-regulated oncolytic herpes virus to target glioma

Zahid M. Delwar _, Guoyu Liu, Yvonne Kuo, Cleo Lee, Luke Bu, Paul S. Rennie and William W. Jia

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Oncotarget. 2016; 7:28658-28669. https://doi.org/10.18632/oncotarget.8637

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Abstract

Zahid M. Delwar1,2,3, Guoyu Liu2,3, Yvonne Kuo3,4, Cleo Lee3, Luke Bu2,3, Paul S. Rennie5, William W. Jia2,3

1Experimental Medicine Program, Department of Medicine, University of British Columbia, Vancouver, Canada

2Department of Surgery, University of British Columbia, Vancouver, Canada

3Brain Research Centre, University of British Columbia, Vancouver, Canada

4Department of Biology, University of British Columbia, Vancouver, Canada

5Department of Urology, University of British Columbia, Vancouver, Canada

Correspondence to:

William W. Jia, email: [email protected]

Keywords: oncolytic herpes virus, glioma, survivin, microRNA, 5’UTR

Received: January 21, 2016     Accepted: March 16, 2016     Published: April 7, 2016

ABSTRACT

Oncolytic herpes simplex virus type 1 (oHSV-1) therapy is an emerging treatment modality that selectively destroys cancer. Here we report use of a glioma specific HSV-1 amplicon virus (SU4-124 HSV-1) to selectively target tumour cells. To achieve transcriptional regulation of the SU4-124 HSV-1 virus, the promoter for the essential HSV-1 gene ICP4 was replaced with a tumour specific survivin promoter. Translational regulation was achieved by incorporating 5 copies of microRNA 124 target sequences into the 3’UTR of the ICP4 gene. Additionally, a 5’UTR of rat fibroblast growth factor -2 was added in front of the viral ICP4 gene open reading frame. Our results confirmed enhanced expression of survivin and eIF4E in different glioma cells and increased micro-RNA124 expression in normal human and mouse brain tissue. SU4-124 HSV-1 had an increased ICP4 expression and virus replication in different glioma cells compared to normal neuronal cells. SU4-124 HSV-1 exerted a strong antitumour effect against a panel of glioma cell lines. Intracranial injection of SU4-124 HSV-1 did not reveal any sign of toxicity on day 15 after the injection. Moreover, a significantly enhanced antitumour effect with the intratumourally injected SU4-124 HSV-1 virus was demonstrated in mice bearing human glioma U87 tumours, whereas viral DNA was almost undetectable in normal organs. Our study indicates that incorporation of multiple cancer-specific regulators in an HSV-1 system significantly enhances both cancer specificity and oncolytic activity.


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