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Regional administration of oncolytic Echovirus 1 as a novel therapy for the peritoneal dissemination of gastric cancer

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Abstract

The dissemination of malignant gastric cells to the peritoneum occurs frequently, usually as an early event in disease, and results in poor patient prognosis. Surgery and chemotherapy offer limited therapeutic success. The low-pathogenic human enterovirus, Echovirus 1 (EV1), is an oncolytic virus that selectively targets and destroys malignant prostate and ovarian cancer xenografts in vivo. Lytic EV1 infection requires the cell surface expression of α2β1, an integrin involved in the dissemination of gastric cancer cells to the peritoneum. Herein, we evaluated the capacity of EV1 for anti-neoplastic cell action in gastric peritoneal carcinomatosis. Flow cytometric analysis demonstrated that α2β1 was abundantly surface expressed on a panel of gastric cancer cell lines, rendering the majority of lines highly susceptible to in vitro lytic EV1 infection and supportive of efficient viral progeny production. A bioluminescent MKN-45-Luc SCID mouse model of peritoneal dissemination was developed to allow real-time non-invasive monitoring of peritoneal tumor burden. Employing this mouse model, we demonstrated a therapeutic dose-response for escalating oncolytic EV1 doses. Taken together, these results emphasize the exciting potential for EV1 as a single or adjunct therapy for the control of the peritoneal dissemination of gastric cancer.

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Acknowledgements

We gratefully acknowledge those investigators mentioned in the text for the provision of monoclonal antibodies, vectors, cell lines, and virus that enabled this study to be undertaken. We would also like to thank Dr Erin O’Neill, Jaclyn Stewart, Elise Mac Pherson, Debbie Pepperall, Matthew Bowman, and Brian Krishnan for their valuable technical assistance throughout the project and Dr E. S. Johansson for revision of the manuscript. Funding for this work was provided by Viralytics Ltd.

Funding

Darren R. Shafren is a director of Viralytics Pty Ltd. Gough G. Au, Richard D. Barry and Darren R. Shafren hold stock of Viralytics Pty Ltd. and are currently conducting research sponsored by this company.

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Authors and Affiliations

  1. The Picornavirus Research Unit, School of Biomedical Sciences, Faculty of Health, The University of Newcastle, Newcastle, NSW, 2300, Australia

    Erin S. Haley, Gough G. Au, Richard D. Barry & Darren R. Shafren

  2. Animal Services Unit, The University of Newcastle, Newcastle, NSW, 2300, Australia

    Brian R. Carlton

  3. Viralytics Ltd, Unit 8, 33 Ryde Road, Pymble, NSW, 2073, Australia

    Darren R. Shafren

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  1. Erin S. Haley
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  2. Gough G. Au
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Correspondence to Darren R. Shafren.

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Haley, E.S., Au, G.G., Carlton, B.R. et al. Regional administration of oncolytic Echovirus 1 as a novel therapy for the peritoneal dissemination of gastric cancer. J Mol Med 87, 385–399 (2009). https://doi.org/10.1007/s00109-008-0433-0

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