Despite continuing advances in target identification and drug development, many approaches only bestow modest clinical benefit, induce a response only in a portion of patients, and/or become inefficient after patients become resistant to therapy. In this project we propose a new RNA therapy approach, using combinations of small non-coding RNAs (siRNAs and related molecules) designed to cross-target components of the RAS-MAPK pathway, a cell signalling cascade that drives oncogenesis by promoting cell growth and survival.
There is tremendous optimism regarding the potential of RNA-based therapies however the concern of immunoreactivity and off-target effects remain. We reduce these risks by combining our small RNAs at low concentration, ensuring that genes of interest are inhibited through their multiple targeting whilst unintended off-targets are minimal and widely distributed.
Using qRT-PCR and western blotting, we demonstrate that combining these small RNAs at sub-nanomolar level exert co-operative effects and efficiently reduce the activity of the RAS pathway, decrease the survival of RAS-dependent cancer cells, and reduce off-targets compared to more traditional approaches using single small RNAs at high concentration. Future work aims to confirm the efficiency of this strategy on tumour growth in vivo.
This work will lead to the validation of multiplexing small RNAs as a potential therapeutic strategy with high specificity and less toxicity to treat drug-resistant cancer cells.