Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression.
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.
Aleku
Manuela
M
Silence Therapeutics AG, Berlin, Germany.
Schulz
Petra
P
Keil
Oliver
O
Santel
Ansgar
A
Schaeper
Ute
U
Dieckhoff
Britta
B
Janke
Oliver
O
Endruschat
Jens
J
Durieux
Birgit
B
Röder
Nadine
N
Löffler
Kathrin
K
Lange
Christian
C
Fechtner
Melanie
M
Möpert
Kristin
K
Fisch
Gerald
G
Dames
Sibylle
S
Arnold
Wolfgang
W
Jochims
Karin
K
Giese
Klaus
K
Wiedenmann
Bertram
B
Scholz
Arne
A
Kaufmann
Jörg
J
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
D008081:Liposomes; D034741:RNA, Small Interfering; C061570:protein kinase N; D011493:Protein Kinase C