MicroRNAs (miRNAs) are a class of non-coding RNAs which repress the translation of mRNA target genes. A handful of miRNAs have already entered early-stage clinical trials in other cancer types.
A genome-wide functional screen of 1280 miRNAs using both miRNA mimics (overexpression) and antisense inhibitors was carried out in two neuroblastoma (NB) cell lines (including MYCN-amplified Kelly). This screen was also performed in the presence of low dose chemotherapy, which allowed us to discover 22 synthetic lethal miRNAs which synergize with chemotherapy, in addition to 114 outright lethal miRNAs. Having validated the majority of these in a secondary screen that included an additional MYCN-amplified cell line (SK-N-DZ), we are now proceeding to investigate mechanisms of action and direct target genes. Through integrating several established bioinformatics tools we can investigate patterns of over-represented target genes/pathways among several miRNAs with similar phenotypes. Clinical relevance of miRNAs and their targets will be examined using datasets from NB tumours with known outcomes. In order to assess the miRNAs in vivo as potential therapeutics we aim to use nanoparticle delivery vectors in patient-derived xenograft models of high-risk NB.