Combining oncolytic adenovirus with radiation—a paradigm for the future of radiosensitization

O'Cathail, S. M. , Pokrovska, T. D., Maughan, T. S., Fisher, K. D., Seymour, L. W. and Hawkins, M. A. (2017) Combining oncolytic adenovirus with radiation—a paradigm for the future of radiosensitization. Frontiers in Oncology, 7, 153. (doi: 10.3389/fonc.2017.00153) (PMID:28791251) (PMCID:PMC5523729)

Abstract

Oncolytic viruses and radiotherapy represent two diverse areas of cancer therapy, utilizing quite different treatment modalities and with non-overlapping cytotoxicity profiles. It is, therefore, an intriguing possibility to consider that oncolytic (“cancer-killing”) viruses may act as cancer-selective radiosensitizers, enhancing the therapeutic consequences of radiation treatment on tumors while exerting minimal effects on normal tissue. There is a solid mechanistic basis for this potential synergy, with many viruses having developed strategies to inhibit cellular DNA repair pathways in order to protect themselves, during genome replication, from unwanted interference by cell processes that are normally triggered by DNA damage. Exploiting these abilities to inhibit cellular DNA repair following damage by therapeutic irradiation may well augment the anticancer potency of the approach. In this review, we focus on oncolytic adenovirus, the most widely developed and best understood oncolytic virus, and explore its various mechanisms for modulating cellular DNA repair pathways. The most obvious effects of the various adenovirus serotypes are to interfere with activity of the MRE11-Rad50-Nbs1 complex, temporally one of the first sensors of double-stranded DNA damage, and inhibition of DNA ligase IV, a central repair enzyme for healing double-stranded breaks by non-homologous end joining (NHEJ). There have been several preclinical and clinical studies of this approach and we assess the current state of progress. In addition, oncolytic viruses provide the option to promote a localized proinflammatory response, both by mediating immunogenic death of cancer cells by oncosis and also by encoding and expressing proinflammatory biologics within the tumor microenvironment. Both of these approaches provide exciting potential to augment the known immunological consequences of radiotherapy, aiming to develop systems capable of creating a systemic anticancer immune response following localized tumor treatment.

• Item Type: Articles
• Additional Information: The authors are grateful to Cancer Research UK and to the Medical Research Council for financial support via the Oxford Institute for Radiation Oncology (refs H3R00390 and H3R00391), for Cancer Research UK programme grant support (ref C552/ A17720) and for Medical Research Council grant support (ref MC_PC_12001/2).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: O'Cathail, Dr Sean
• Authors: O'Cathail, S. M., Pokrovska, T. D., Maughan, T. S., Fisher, K. D., Seymour, L. W., and Hawkins, M. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Frontiers in Oncology
• Publisher: Frontiers Media
• ISSN: 2234-943X
• ISSN (Online): 2234-943X
• Copyright Holders: Copyright © 2017 O’Cathail, Pokrovska, Maughan, Fisher, Seymour and Hawkins
• First Published: First published in Frontiers in Oncology 7: 153
• Publisher Policy: Reproduced under a Creative Commons License