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A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Δ24, for the treatment of advanced breast cancer

Gene Therapy volume 14, pages 58–67 (2007)Cite this article

Abstract

Conditionally replicating adenoviruses (CRAds) that replicate in tumor but less in normal cells are promising anticancer agents. A major determinant of their potency is their capacity for infecting target cells. The primary receptor for serotype 5 adenovirus (Ad5), the most widely used serotype in gene therapy, is the coxsackie-adenovirus receptor (CAR). CAR is expressed variably and often at low levels in various tumor types including advanced breast cancer. We generated a novel p16/retinoblastoma pathway-dependent CRAd, Ad5.pK7-Δ24, with a polylysine motif in the fiber C-terminus, enabling CAR-independent binding to heparan sulfate proteoglycans (HSPG). Ad5.pK7-Δ24 mediated effective oncolysis of all breast cancer cell lines tested. Further, we utilized noninvasive, fluorescent imaging for analysis of antitumor efficacy in an orthotopic model of advanced hormone refractory breast cancer. A therapeutic benefit was seen following both intratumoral and intravenous delivery. Murine biodistribution similar to Ad5, proven safe in trials, suggests feasibility of clinical safety testing. Interestingly, upregulation of CAR was seen in low-CAR M4A4-LM3 breast cancer cells in vivo, which resulted in better than expected efficacy also with an isogenic CRAd with an unmodified capsid. These results suggest utility of Ad5.pK7-Δ24 and the orthotopic model for further translational studies.

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Acknowledgements

This study was supported by HUCH Research Funds (EVO), Academy of Finland, Emil Aaltonen Foundation, Finnish Cancer Society, University of Helsinki, Sigrid Juselius Foundation, Helsinki Biomedical Graduate School, EU FP6 THERADPOX, Sohlberg Foundation, Biocentrum Helsinki, Instrumentarium Research Fund, Research and Science Foundation Farmos, the Finnish Breast Cancer Group and the Finnish Oncology Association.

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Authors and Affiliations

  1. Cancer Gene Therapy Group, Rational Drug Design Program and Haartman Institute, University of Helsinki, Helsinki, Finland

    T Ranki, A Kanerva, T Hakkarainen, M Särkioja, L Kangasniemi, M Raki & A Hemminki

  2. Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland

    T Ranki, A Kanerva, T Hakkarainen, M Särkioja, L Kangasniemi, M Raki & A Hemminki

  3. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

    A Kanerva

  4. Pathology/HUSLAB, Helsinki University Central Hospital, Helsinki, Finland

    A Ristimäki

  5. Molecular and Cancer Research Biology Program, University of Helsinki, Helsinki, Finland

    A Ristimäki & P Laakkonen

  6. Department of Pathology, University of Florida, Jacksonville, FL, USA

    S Goodison

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Correspondence to A Hemminki.

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Ranki, T., Kanerva, A., Ristimäki, A. et al. A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Δ24, for the treatment of advanced breast cancer. Gene Ther 14, 58–67 (2007). https://doi.org/10.1038/sj.gt.3302830

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