title: Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression.
abstract: 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.
authors.affiliation: Silence Therapeutics AG, Berlin, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Aleku
authors.forename: Petra
authors.initials: P
authors.lastname: Schulz
authors.forename: Oliver
authors.initials: O
authors.lastname: Keil
authors.forename: Ansgar
authors.initials: A
authors.lastname: Santel
authors.forename: Ute
authors.initials: U
authors.lastname: Schaeper
authors.forename: Britta
authors.initials: B
authors.lastname: Dieckhoff
authors.forename: Oliver
authors.initials: O
authors.lastname: Janke
authors.forename: Jens
authors.initials: J
authors.lastname: Endruschat
authors.forename: Birgit
authors.initials: B
authors.lastname: Durieux
authors.forename: Nadine
authors.initials: N
authors.lastname: Röder
authors.forename: Kathrin
authors.initials: K
authors.lastname: Löffler
authors.forename: Christian
authors.initials: C
authors.lastname: Lange
authors.forename: Melanie
authors.initials: M
authors.lastname: Fechtner
authors.forename: Kristin
authors.initials: K
authors.lastname: Möpert
authors.forename: Gerald
authors.initials: G
authors.lastname: Fisch
authors.forename: Sibylle
authors.initials: S
authors.lastname: Dames
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Arnold
authors.forename: Karin
authors.initials: K
authors.lastname: Jochims
authors.forename: Klaus
authors.initials: K
authors.lastname: Giese
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Arne
authors.initials: A
authors.lastname: Scholz
authors.forename: Jörg
authors.initials: J
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D008207:Lymphatic Metastasis; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D051381:Rats; D014162:Transfection / Q000379:methods
chemical_list: D008081:Liposomes; D034741:RNA, Small Interfering; C061570:protein kinase N; D011493:Protein Kinase C