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Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

¹ Silence Therapeutics AG; ² Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin, Berlin, Germany; and ³ IASON Consulting, Niederzier, Germany

Requests for reprints: Jörg Kaufmann, Silence Therapeutics AG, Otto-Warburg Haus, Robert-Rössle-Strasse 10, Berlin 13125, Germany. Phone: 49-30-9489-2833; Fax: 49-30-9489-2801; E-mail: j.kaufmann{at}silence-therapeutics.com.

Key Words: cancer therapeutic • RNA interference • siRNA delivery

We have previously described a small interfering RNA (siRNA) delivery system (AtuPLEX) for RNA interference (RNAi) in the vasculature of mice. Here we report preclinical data for Atu027, a siRNA-lipoplex directed against protein kinase N3 (PKN3), currently under development for the treatment of advanced solid cancer. In vitro studies revealed that Atu027-mediated inhibition of PKN3 function in primary endothelial cells impaired tube formation on extracellular matrix and cell migration, but is not essential for proliferation. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates results in specific, RNAi-mediated silencing of PKN3 expression. We show the efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density. [Cancer Res 2008;68(23):9788–98]