DNAzyme targeting c-jun suppresses skin cancer growth.
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.
Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia.
Hong
H
Cai
Fernando S
FS
Santiago
Leonel
L
Prado-Lourenco
Bo
B
Wang
Margaret
M
Patrikakis
Miles P
MP
Davenport
Ghassan J
GJ
Maghzal
Roland
R
Stocker
Christopher R
CR
Parish
Beng H
BH
Chong
Graham J
GJ
Lieschke
Tak-Wah
TW
Wong
Colin N
CN
Chesterman
Douglas J
DJ
Francis
Fergal J
FJ
Moloney
Ross St C
RS
Barnetson
Gary M
GM
Halliday
Levon M
LM
Khachigian
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D021881:DNA, Catalytic / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D051379:Mice; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy*; D015027:Zebrafish
D021881:DNA, Catalytic; D016755:Proto-Oncogene Proteins c-jun