Abstract B204: Development of ALN‐VSP: An RNAi therapeutic for liver malignancies

Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. We are developing a therapeutic for solid tumors involving the liver that is comprised of lipid particle‐formulated small interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. To assess efficacy in vivo , a stable nucleic acid lipid particle (SNALP) formulation was developed based on similar formulations previously shown to silence liver‐expressed genes via systemic administration in multiple species. A SNALP‐formulated combination of the KSP and VEGF siRNAs (referred to as ALN‐VSP) was tested in orthotopic liver tumor models in which human tumor cells are implanted directly into the livers of immunocompromised mice. We show that intravenous administration of ALN‐VSP leads to silencing of both KSP and VEGF expression in established liver tumors. This is accompanied by the formation of numerous aberrant mitotic figures (“monoasters”) in tumor cells indicative of the pharmacologic inhibition of KSP. In addition, we demonstrate that ALN‐VSP treatment provides a clear survival benefit even when treatment is initiated in animals with a significant tumor burden. A Phase 1 clinical trial of ALN‐VSP has recently been initiated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B204.