Targeting c-Jun with the DNAzyme Dz13 for therapy of human basal cell carcinoma — ASN Events

Targeting c-Jun with the DNAzyme Dz13 for therapy of human basal cell carcinoma (#139)

Gary M Halliday 1 , Eun-Ae Cho 1 , Hong Cai 2 , Fergal J Moloney 1 3 , Douglas J Francis 4 , Richard A Scolyer 5 , Levon M Khachigian 2
  1. Dermatology Bosch Institute, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW, Australia
  2. Center for Vascular Research, University of New South Wales, Sydney, NSW, Australia
  3. Present address Dermatology, Mater Misericordiae University Hospital, Dublin, Republic of Ireland, Ireland
  4. DF Pre-clinical Services Pty Ltd, Canberra, ACT, Australia
  5. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

Similar to many other cancers, human basal cell carcinoma (BCC) expresses high levels of the transcription factor c-Jun. It is expressed at low levels in normal tissue, making it an ideal target for skin cancer therapy. DNAzymes are a promising new class of therapeutic. Their use has not previously been reported in humans. These single-stranded, all DNA, catalytic molecules bind their target RNA via Watson-Crick base pairing and cleave the RNA. Dz13 is a DNAzyme that cleaves mRNA of c-Jun (1). Intra-tumoural injection of Dz13, but not scrambled control, induced complete inhibition of murine squamous cell carcinoma (SCC) and human BCC lines growing in immunodeficient mice. The mechanism involved inhibition of neovascularization and induction of apoptosis. Dz13 had a more pronounced effect and induced regression in immunocompetent mice as it also activated T cell mediated immunity. In toxicology studies compliant with good laboratory practice, Dz13 administered to cynomolgus monkeys, minipigs and rodents was found to be safe and well tolerated (2). We conducted a first-in-class, first-in-human clinical trial to determine the safety of Dz13. Nine subjects with nodular BCC received a single intra-tumoural injection of Dz13 in 3 escalating dose groups. No drug-related serious adverse events occurred during administration or follow up. There was no detectable systemic Dz13 in blood samples. Reduced c-Jun expression was observed in the BCC removed 2 weeks following injection compared to pre-treatment biopsies. There was also an increase in T cell infiltration and markers of apoptosis. This study has demonstrated the potential for Dz13 as a safe, novel cancer therapeutic in human BCC. Furthermore, it inhibited its target, c-Jun, and activated the immune and apoptotic mechanisms found to be responsible for tumour regression in pre-clinical studies.

  1. Khachigian et al. Oncotarget 2012: 3: 594-595.
  2. Cai H et al. Science translational medicine 2012: 4: 139ra182.