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Combining virotherapy and angiotherapy for the treatment of breast cancer

Cancer Gene Therapy volume 20, pages 461–468 (2013)Cite this article

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Abstract

A breast cancer-selective oncolytic adenovirus was engineered to express antagonists of vascular endothelial growth factor (VEGF) and Notch signaling to combine direct anticancer activity with disruption of tumor-associated angiogenesis. Replication of the parental virus, AdEHE2F, is stimulated by estrogen receptor (ER), E2F1 and hypoxia, and it mediates selective lysis of breast cancer cells in vitro and in vivo. Here, we encoded soluble Flt-1 (sFlt1) and soluble Dll4 (sDll4) under control of the E3 promoter. sFlt1 (the extra-cellular domain of VEGF receptor 1) binds VEGF-A and inhibits stimulation of VEGFR2, decreasing angiogenic stimulus. Conversely, sDll4 (the extracellular domain of Delta-like 4) antagonizes Notch signaling to prevent endothelial maturation. We hypothesized that these agents might show additive or synergistic activity. In vitro, sFlt1 inhibited endothelial cell proliferation and sprouting, whereas sDll4 increased the number of vascular branchpoints. In ER-positive ZR75.1 tumors in vivo AdEHE2F showed the potent direct virotherapy with no augmentation owing to sFlt1 or sDll4; however, in ER-negative MDA-231 tumors efficacy was enhanced by encoding sFlt1 or sDll4, with survival time extending to double that of controls. There was also a dramatic decrease in the total number of tumour blood vessels, as well as the number of perfused vessels, suggesting that improved efficacy reflects combined anti-tumour and anti-vascular effects.

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Acknowledgements

We gratefully acknowledge the support of the Clarendon Fund, Balliol and Magdalen Colleges, University of Oxford and the Consejo Nacional de Ciencia y Tecnologia (CONACYT) (MBP), European Union (RCC, LSHB-CT-2004-512087) and Cancer Research UK (LWS), technical histology services provided by Louise Young and Hilary Brown, and Fionnadh Carroll for technical support in animal experimentation.

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Authors and Affiliations

  1. Department of Oncology, Old Road Campus, University of Oxford, Oxford, UK

    M Bazan-Peregrino, C Thoma & L W Seymour

  2. Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    R C A Sainson & A L Harris

  3. Institute of Biomedical Engineering, Old Road Campus, University of Oxford, Oxford, UK

    R C Carlisle & C Arvanitis

  4. Centre for Statistics in Medicine, University of Oxford, Oxford, UK

    R A Waters

  5. Division of Hepatology and Gene Therapy, School of Medicine, Foundation for Applied Medical Research, University of Navarra, CIMA, Pamplona, Spain

    R Hernandez-Alcoceba

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  1. M Bazan-Peregrino
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Correspondence to L W Seymour.

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Bazan-Peregrino, M., Sainson, R., Carlisle, R. et al. Combining virotherapy and angiotherapy for the treatment of breast cancer. Cancer Gene Ther 20, 461–468 (2013). https://doi.org/10.1038/cgt.2013.41

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