Oncolytic Vaccinia virus safely and effectively treats skin tumors in mouse models of xeroderma pigmentosum

Authors

  • Jan Brun,

    1. Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
    2. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada
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  • Douglas J. Mahoney,

    1. Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
    2. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada
    Current affiliation:
    1. Alberta Children's Hospital Research Institute, Calgary, AB, T2N 4N1, Canada
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  • Fabrice Le Boeuf,

    1. Ottawa Hospital Research Institute, Center for Cancer Therapeutics, 501 Smyth Road, 3rd Floor, box 926, Ottawa, Ontario, K1H8L6
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  • Charles Lefebvre,

    1. Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
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  • Cina A. Sanaei,

    1. Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
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  • Theresa Falls,

    1. Ottawa Hospital Research Institute, Center for Cancer Therapeutics, 501 Smyth Road, 3rd Floor, box 926, Ottawa, Ontario, K1H8L6
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  • J. Andrea Mccart,

    1. Division of Experimental Therapeutics, Toronto General Research Institute of Surgery, and the Department of Surgery Mount Sinai Hospital, Toronto, Canada
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  • David F. Stojdl

    Corresponding author
    1. Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
    2. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada
    3. Department of Pediatrics, University of Ottawa, Ottawa, ON K1H 8L1, Canada
    • Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1
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    • Tel.: +613-738-4179, Fax: +613-738-4833


Abstract

Xeroderma pigmentosum (XP) is an orphan autosomal recessive disorder of DNA repair. When exposed to genotoxic stress, XP patients have reduced capacity to remove bulky adducts by nucleotide excision repair and are thus greatly predisposed to cancer. Unfortunately, given the nature of their underlying genetic defect, tumor-bearing XP patients cannot be treated with conventional DNA damaging therapies. Engineered strains of the poxvirus Vaccinia have been shown to cure cancer in numerous preclinical models, and based on promising Phase I/II clinical trials have recently been approved for late phase evaluation in humans. As poxviruses are nongenotoxic, we investigated whether clinical-candidate strains of Vaccinia can safely and effectively treat cancers arising from XP. In vitro, Vaccinia virus was highly cytotoxic against tumor-derived cells from XP patients, on average 10- to 100-fold more so than on nontumor derived control cells from similar patients. In vivo, local or systemic administration of Vaccinia virus led to durable tumor resolution in both xenograft and genetic models of XP. Importantly, Vaccinia virus was well tolerated in the genetic models, which are each null for a critical component of the DNA repair process. Taken together, our data suggest that oncolytic Vaccinia virus may be a safe and effective therapy for cancers arising from XP, and raise the possibility of similar therapeutic potential against tumors that arise in patients with other DNA repair disorders.

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