Systemic Delivery of an Oncolytic Adenovirus Expressing Decorin for the Treatment of Breast Cancer Bone Metastases.

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.

• Authors: 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
• Journal: Human gene therapy (Hum Gene Ther) Vol. 26 Issue 12 Pg. 813-25 (Dec 2015) ISSN: 1557-7422 [Electronic] United States
• PMID: 26467629 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CTNNB1 protein, mouse
• Dcn protein, mouse
• Decorin
• Vascular Endothelial Growth Factor A
• beta Catenin
• vascular endothelial growth factor A, mouse
• Luciferases
• Proto-Oncogene Proteins c-met

Topics

• Adenoviridae (genetics, metabolism)
• Animals
• Bone Neoplasms (genetics, metabolism, secondary, therapy)
• Bone Resorption (genetics, metabolism, pathology, prevention & control)
• Bone and Bones (metabolism, pathology)
• Decorin (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Genetic Vectors (chemistry, metabolism)
• Humans
• Luciferases (genetics, metabolism)
• Mammary Neoplasms, Experimental (genetics, metabolism, pathology, therapy)
• Mice
• Mice, Nude
• Oncolytic Virotherapy (methods)
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• Signal Transduction
• Transgenes
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• beta Catenin (genetics, metabolism)