Abstract
Oncolytic adenoviruses are a promising treatment alternative for many advanced cancers, including colorectal cancer. However, clinical trials have demonstrated that single-agent therapy in advanced tumor masses is rarely curative. Poor spreading of the virus through tumor tissue is one of the major issues limiting efficacy. As oncolytic viruses kill preferentially cancer cells, high extracellular matrix (ECM) content constitutes potential barriers for viral penetration within tumors. In this study, the ECM-degrading proteases relaxin, hyaluronidase, elastase and macrophage metalloelastase (MME) were tested for their antitumor efficacy alone and in combination with oncolytic adenovirus. MME improved the overall antitumor efficacy of oncolytic adenovirus in subcutaneous HCT116 xenografts. In a liver metastatic colorectal cancer model, intra-tumoral treatment of primary tumors from HT29 cells with MME monotherapy or with oncolytic adenovirus inhibited tumor growth. Combination therapy showed no increased mortality in comparison with either monotherapy alone. Contradictory results of effects of MME on tumorigenesis and metastasis formation have been reported in the literature. This study demonstrates for the first time in a metastatic animal model that MME, as a monotherapy or in combination with oncolytic virus, does not increase tumor invasiveness. Co-administration of MME and oncolytic adenovirus may be a suitable approach for further optimization aiming at clinical applications for metastatic colorectal cancer.
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Acknowledgements
We thank Dr Dennis R Stewart (Principal Scientist; Corthera Inc.) for providing relaxin for this study. AH is K Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute. This paper was supported by the European Research Council, EU FP6 APOTHERAPY and THERADPOX, the ASCO Foundation, HUCH Research Funds (EVO), the Sigrid Juselius Foundation, Academy of Finland, Biocentrum Helsinki, Biocenter Finland, University of Helsinki. AH is founder and shareholder in Oncos Therapeutics Ltd.
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Lavilla-Alonso, S., Bauer, M., Abo-Ramadan, U. et al. Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development. Cancer Gene Ther 19, 126–134 (2012). https://doi.org/10.1038/cgt.2011.76
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DOI: https://doi.org/10.1038/cgt.2011.76
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