Abstract 1153P
Background
Lung cancer is one of the leading causes of cancer related deaths world-wide. The introduction of targeted therapies such as immune-checkpoint inhibitors has seen great improvement in patient survival, with 5-year survival increasing substantially. However, in the advanced setting many lung cancer patients have extremely poor 5-year survival rates. There is, therefore, a great need for more effective and less toxic cancer therapeutics. We have developed a first in class oligonucleotide therapeutic named DKLS02 that targets the DNA repair protein hSSB1. hSSB1 functions in double strand break repair and in the repair of oxidative damage. As hSSB1 is overexpressed in solid tumours the DNA repair protein may represent a novel target for therapy in non-small cell lung cancer (NSCLC).
Methods
We interrogated publicly available datasets to evaluate the prognostic significance of hSSB1 expression in NSCLC. We also performed immunohistochemistry on tissue microarrays from 2 patient cohorts using an in-house polyclonal antibody. We used in vitro cell viability assay and in vivo lung cancer xenograft models to test the efficacy of DKLS02. The safety of DKLS02 was assessed in repeat-dose GLP toxicology studies in rodent (mouse) and non-rodent (Beagle dog) models.
Results
hSSB1 is associated with a poor prognosis in NSCLC. siRNA-mediated depletion of hSSB1 inhibits cell proliferation in lung cancer cell lines. DKLS02 suppresses cisplatin sensitive and resistant NSCLC cell line growth in vitro and in lung cancer xenografts. DKLS02 has a favourable pharmacokinetic and pharmacodynamic profile fit for evaluation in phase I clinical trials.
Conclusions
hSSB1 over-expression is associated with a poor prognosis in NSCLC at both the mRNA and protein level. DKLS02 treatment inhibits proliferation of lung cancer cell lines in vitro and induces tumour growth suppression in lung cancer xenograft studies in mice. DKLS02 has a favourable toxicology profile and a phase Ia, open label, dose escalation and expansion study is planned in patients with advanced tumours.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
RepLuca Pharmaceuticals Pty Ltd.
Funding
RepLuca Pharmaceuticals Pty Ltd; Cancer and Ageing Research Program QUT.
Disclosure
D.J. Richard, K.J. O'Byrne: Financial Interests, Personal, Stocks/Shares: RepLuca Pharmaceuticals. All other authors have declared no conflicts of interest.