Abstract 581: Development of RNA interference-based therapeutics for bladder cancer and hepatocellular carcinoma

Abstract

Abstract Bladder cancer and hepatocellular carcinoma are two of many cancers refractory to current treatments. Small interfering RNAs (siRNAs) are a new therapeutic modality able to specifically silence expression of targets not accessible via current small molecule and antibody options. MDRNA is developing UsiRNAs, a novel siRNA construct containing unlocked nucleobase analogs, with improved specificity for RNA interference (RNAi). Delivery of UsiRNAs to target tissues is achieved using proprietary Di-alkylated Amino Acid (DiLA2)-based liposomes. Survivin, overexpressed in many cancers, is involved in cell division and inhibition of apoptosis. In orthotopic and xenograft models of liver cancer, systemic administration of survivin UsiRNA-DiLA2 liposomes resulted in approximately 60% and 70% reductions in survivin mRNA, respectively, and > 50% decreases in tumor weight. Local intravesical administration in an orthotopic bladder cancer model resulted in 90% inhibition of mRNA expression and substantial tumor growth inhibition. Polo-like kinase 1 (PLK-1), also elevated in many tumors, regulates cell cycle progression and mitosis. Treatment of bladder cancer and liver cancer cell lines with PLK-1 UsiRNA/DiLA2 liposomes leads to significant caspase activation and corresponding apoptotic cell death. In vivo studies with PLK-1 UsiRNA are in progress. These UsiRNAs and UsiRNAs directed against additional targets are being evaluated in vitro and in orthotopic and xenograft models of cancer as single agents, in combinations of target-specific UsiRNAs, and with existing small molecule and antibody therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 581.