Systemic delivery of an oncolytic adenovirus expressing decorin for the treatment of breast cancer bone metastases

Yuefeng Yang, Weidong Xu, Thomas Neill, Zebin Hu, Chi Hsiung Wang, Xianghui Xiao, Stuart R. Stock, Theresa Guise, Chae Ok Yun, Charles B. Brendler, Renato V. Iozzo, Prem Seth

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The development of novel therapies for breast cancer bone metastasis is a major unmet medical need. Toward that end, we have constructed an oncolytic adenovirus, Ad.dcn, and a nonreplicating adenovirus, Ad(E1-).dcn, both containing the human decorin gene. Our in vitro studies showed that Ad.dcn produced high levels of viral replication and the decorin protein in the breast tumor cells. Ad(E1-).dcn-mediated decorin expression in MDA-MB-231 cells downregulated the expression of Met, β-catenin, and vascular endothelial growth factor A, all of which are recognized decorin targets and play pivotal roles in the progression of breast tumor growth and metastasis. Adenoviral-mediated decorin expression inhibited cell migration and induced mitochondrial autophagy in MDA-MB-231 cells. Mice bearing MDA-MB-231-luc skeletal metastases were systemically administered with the viral vectors, and skeletal tumor growth was monitored over time. The results of bioluminescence imaging and X-ray radiography indicated that Ad.dcn and Ad(E1-).dcn significantly inhibited the progression of bone metastases. At the terminal time point, histomorphometric analysis, micro-computed tomography, and bone destruction biomarkers showed that Ad.dcn and Ad(E1-).dcn reduced tumor burden and inhibited bone destruction. A nonreplicating adenovirus Ad(E1-).luc expressing the luciferase 2 gene had no significant effect on inhibiting bone metastases, and in several assays, Ad.dcn and Ad(E1-).dcn were better than Ad.luc, a replicating virus expressing the luciferase 2 gene. Our data suggest that adenoviral replication coupled with decorin expression could produce effective antitumor responses in a MDA-MB-231 bone metastasis model of breast cancer. Thus, Ad.dcn could potentially be developed as a candidate gene therapy vector for treating breast cancer bone metastases.

Original languageEnglish (US)
Pages (from-to)813-825
Number of pages13
JournalHuman gene therapy
Volume26
Issue number12
DOIs
StatePublished - Dec 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Yang, Y., Xu, W., Neill, T., Hu, Z., Wang, C. H., Xiao, X., Stock, S. R., Guise, T., Yun, C. O., Brendler, C. B., Iozzo, R. V., & Seth, P. (2015). Systemic delivery of an oncolytic adenovirus expressing decorin for the treatment of breast cancer bone metastases. Human gene therapy, 26(12), 813-825. https://doi.org/10.1089/hum.2015.098