Abstract B15: In vivo analysis of repeated siRNA silencing on protein expression levels

An ever increasing number of anticancer drugs are under investigation, and enter the clinical setting targeting different tumor survival and/or growth mechanisms; however, development of resistance against the mechanism of action of even the most promising drugs seems to be inevitable and remains a major concern. RNA interference (RNAi) have shown considerable promise in silencing proteins involved in tumor vascularization, as well as intracellular pathways involved in cell proliferation and/or survival. Despite the apparent efficacy of this powerful tool (especially in vitro), our information about the factors affecting siRNA efficiency and the possibility of resistance development against the silencing effect are limited at best. This study focused on determining the possibility of resistance development against siRNA treatment as a result of repeated exposure to siRNA in vivo. Our preliminary experiments in vitro revealed an unaffected siRNA cellular internalization and reproducible silencing efficiency of selected targets. The expression level of other mediators involved in breast cancer cell survival and proliferation (notably survivin, JUN, JAK2, NFkB and STAT3) were, however, altered in siRNA treated cells. In vivo experiments in a xenograft model demonstrated a similar silencing efficiency at the mRNA level after each repeated dose, with little, if any, apparent resistance development to the siRNA therapy. We conclude that cells would respond to repeated siRNA treatments in a similar fashion after a temporary initial alteration. Citation Format: Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Hasan Uludag. In vivo analysis of repeated siRNA silencing on protein expression levels. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B15.