Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone metastasis in a prostate cancer mouse model

Zebin Hu, Janhavi Gupta, Zhenwei Zhang, Helen Gerseny, Arthur Berg, Yun Ju Chen, Zhiling Zhang, Hongyan Du, Charles B. Brendler, Xianghui Xiao, Kenneth J. Pienta, Theresa Guise, Chung Lee, Paula H. Stern, Stuart Stock, Prem Seth

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

We have examined whether Ad.sTβRFc and TAd.sTβRFc, two oncolytic viruses expressing soluble transforming growth factor-β receptor II fused with human Fc (sTGFβRIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sTβRFc and TAd.sTβRFc produced sTGFβRIIFc and viral replication; sTGFβRIIFc caused inhibition of TGF-β-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sTβRFc, an E1- adenovirus, produced sTGFβRIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5×10 10 viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sTβRFc, TAd.sTβRFc, and Ad(E1-).sTβRFc caused significant inhibition of tumor growth; however, Ad.sTβRFc was the most effective among all the vectors. Only Ad.sTβRFc and TAd.sTβRFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sTβRFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sTβRFc and TAd.sTβRFc can be developed as potential new therapies for prostate cancer bone metastasis.

Original languageEnglish (US)
Pages (from-to)871-882
Number of pages12
JournalHuman gene therapy
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2012

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Hu, Z., Gupta, J., Zhang, Z., Gerseny, H., Berg, A., Chen, Y. J., Zhang, Z., Du, H., Brendler, C. B., Xiao, X., Pienta, K. J., Guise, T., Lee, C., Stern, P. H., Stock, S., & Seth, P. (2012). Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone metastasis in a prostate cancer mouse model. Human gene therapy, 23(8), 871-882. https://doi.org/10.1089/hum.2012.040