DNAzyme targeting c-jun suppresses skin cancer growth

Hong Cai, Fernando S. Santiago, Leonel Prado-Lourenco, Bo Wang, Margaret Patrikakis, Miles P. Davenport, Ghassan J. Maghzal, Roland Stocker, Christopher R. Parish, Beng H. Chong, Graham J. Lieschke, Tak Wah Wong, Colin N. Chesterman, Douglas J. Francis, Fergal J. Moloney, Ross St C. Barnetson, Gary M. Halliday, Levon M. Khachigian

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Abstract

Worldwide, one in three cancers is skin-related, with increasing incidence in many populations. Here, we demonstrate the capacity of a DNAzyme-targeting c-jun mRNA, Dz13, to inhibit growth of two common skin cancer types - basal cell and squamous cell carcinomas - in a therapeutic setting with established tumors. Dz13 inhibited tumor growth in both immunodeficient and immunocompetent syngeneic mice and reduced lung nodule formation in a model of metastasis. In addition, Dz13 suppressed neovascularization in tumor-bearing mice and zebrafish and increased apoptosis of tumor cells. Dz13 inhibition of tumor growth, which required an intact catalytic domain, was due in part to the induction of tumor immunity. In a series of good laboratory practice-compliant toxicology studies in cynomolgus monkeys, minipigs, and rodents, the DNAzyme was found to be safe and well tolerated. It also did not interfere in more than 70 physiologically relevant in vitro bioassays, suggesting a reduced propensity for off-target effects. If these findings hold true in clinical trials, Dz13 may provide a safe, effective therapy for human skin cancer.

Original languageEnglish
Article number139ra82
JournalScience Translational Medicine
Volume4
Issue number139
DOIs
Publication statusPublished - 2012 Jun 20

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All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Cai, H., Santiago, F. S., Prado-Lourenco, L., Wang, B., Patrikakis, M., Davenport, M. P., Maghzal, G. J., Stocker, R., Parish, C. R., Chong, B. H., Lieschke, G. J., Wong, T. W., Chesterman, C. N., Francis, D. J., Moloney, F. J., Barnetson, R. S. C., Halliday, G. M., & Khachigian, L. M. (2012). DNAzyme targeting c-jun suppresses skin cancer growth. Science Translational Medicine, 4(139), [139ra82]. https://doi.org/10.1126/scitranslmed.3003960