Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 39, Pages 14981-14986Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0803988105
Keywords
HDAC inhibitor; oncolytic virus; refractory tumors; combination therapy
Categories
Funding
- National Cancer Institute of Canada, the Canadian Institutes for Health Research
- Terry Fox Foundation
- Cancer Research Society
- Fonds de la Recherche en Sante' du Quebec
- Natural Sciences and Engineering Research Council
- Canadian Institutes of Health Research
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Intratumoral innate immunity can play a significant role in blocking the effective therapeutic spread of a number of oncolytic viruses (OVs). Histone deacetylase inhibitors (HDIs) are known to influence epigenetic modifications of chromatin and can blunt the cellular antiviral response. We reasoned that pretreatment of tumors with HDIs could enhance the replication and spread of OVs within malignancies. Here, we show that HDIs markedly enhance the spread of vesicular stomatitis virus (VSV) in a variety of cancer cells in vitro, in primary tumor tissue explants and in multiple animal models. This increased oncolytic activity correlated with a dampening of cellular IFN responses and augmentation of virus-induced apoptosis. These results illustrate the general utility of HDIs as chemical switches to regulate cellular innate antiviral responses and to provide controlled growth of therapeutic viruses within malignancies. HDIs could have a profoundly positive impact on the clinical implementation of OV therapeutics.
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