Abstract 2829: Preclinical characterization of TKM-080301, a lipid nanoparticle formulation of a small interfering RNA directed against polo-like kinase 1

Small interfering RNAs (siRNAs) have tremendous potential for the selective inhibition, or ‘silencing’, of genes involved in cancer cell growth and division. This inhibition occurs through a process known as RNA interference (RNAi). Polo-like kinase 1 (PLK1) is a target that has multiple critical roles in cell cycle regulation and cytokinesis. Here we describe the preclinical characterization of TKM-080301, a lipid nanoparticle (LNP) formulation of an siRNA directed against human PLK1 mRNA. Studies were performed to assess the in vitro pharmacologic activity and inherent immune stimulatory potential of various siRNAs. PLK1 siRNA formulated in LNP resulted in potent anti-proliferative activity and gene-specific silencing in many cancer cell lines; and TKM-080301 exhibited strong anti-tumor activity in several xenograft models of human cancer, including tumors implanted intra-hepatically and subcutaneously. RNAi and the intended pharmacologic effects were confirmed in these models by histopathology, to visualize mitotic disruption, and by molecular methods, to confirm the presence of the RNAi-induced PLK1 mRNA cleavage product, the degree of PLK1 silencing relative to housekeeping genes, and the duration of silencing. In vivo, PLK1 silencing persisted for up to 7-10 days after a single administration and, importantly, occurred in the absence of any measurable stimulation of the innate immune system. Finally, unlike most small molecule PLK1 inhibitors, which are highly myelosuppresive, the toxicity profile of TKM-080301 was governed by the distribution profile of the LNP and toxicity was largely restricted to the liver and spleen. Collectively, these studies support the clinical evaluation of TKM-080301 as a new approach to targeting PLK1 in solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2829. doi:10.1158/1538-7445.AM2011-2829