Intravesically administered antisense oligonucleotides targeting heat‐shock protein‐27 inhibit the growth of non‐muscle‐invasive bladder cancer

Abstract

To evaluate the inhibitory effects of a second-generation antisense oligonucleotide (ASO) targeting the cytoprotective chaperone heat-shock protein (HSP)-27 (OGX-427, OncoGeneX Technologies, Vancouver, Canada) on human bladder cancer growth both in vitro and in vivo as an intravesical agent in an orthotopic murine model. Human KU-7 bladder tumour cells were treated with OGX-427 or a mismatch (MM) control oligodeoxynucleotide (ODN) in vitro and were assessed for HSP27 expression, proliferation and apoptosis. KU-7-luc cells that stably express luciferase were inoculated in female nude mice by intravesical instillation and tumour size was measured using bioluminescence imaging. Mice with established KU-7-luc tumours were administered uncomplexed 'naked' OGX-427 or MM ODN as well as controlled-release microparticulate chitosan/oligonucleotide formulations intravesically. Tumour growth was monitored over time and tumours were analysed after death using immunohistochemistry and Western blotting. In vitro, OGX-427 significantly decreased HSP27 protein levels and cellular viability. While naked OGX-427 showed only a trend in tumour suppression compared with MM ODN, OGX-427 complexed with chitosan significantly inhibited orthotopic tumour growth. The chitosan preparation induced some haematuria compared to naked ASO, but this formulation had superior tissue uptake of oligonucleotides and suppressed HSP27 tissue levels by 75%. Intravesical OGX-427 instillation therapy showed promising antitumour activity and minimal toxicity in an orthotopic mouse model of high-grade bladder cancer. These findings provide pre-clinical proof-of-principle for the use of ASO as intravesical agents for non-muscle-invasive bladder cancer, and warrant further evaluation of efficacy and safety in early-phase clinical trials.