siRNA Versus shRNA for Personalized Cancer Therapy: Mechanisms and Applications

Abstract

RNA interference (RNAi) is a natural process of gene regulation that can be harnessed to knock down gene and protein targets with high specificity and selectivity. Proteomic and genomic approaches to target identification will soon allow investigators to rapidly indentify biorelevant cancer signal transduction network hubs that are more likely to be susceptible to a therapeutically effective targeted attack by RNAi. At present, the principle methods of mediating the RNAi effect involve synthetic small interfering RNA (siRNA) oligomers and DNA vector driven expression of short hairpin RNA (shRNA). Both these methods can achieve robust and specific knockdown, but they have striking mechanistic differences with broad practical implications. shRNA can effectively target knockdown with low copy numbers and longer lasting effects than siRNA. Bifunctional design has similar benefits to standard shRNA but with greatly enhanced potency. Effective delivery and avoidance of unwanted off-target effects remain as challenges to the clinical development of siRNA and shRNA. This chapter compares and contrasts siRNA, shRNA, and bifunctional shRNA as candidates for personalized solid tumor therapeutics.