title: Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin.
abstract: The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level and therefore can be applied to previously undruggable targets. Lipid nanoparticles (LNP) represent an elegant solution for the delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens, and identify efficacious combinations with standard-of-care therapeutics. Mol Cancer Ther; 15(9); 2143-54. ©2016 AACR.
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts. sganesh@dicerna.com.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Ganesh
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Koser
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Cyr
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Girish R
authors.initials: GR
authors.lastname: Chopda
authors.affiliation: University of Pittsburgh Medical Center, Pittsburgh, Pittsburgh.
authors.forename: Junyan
authors.initials: J
authors.lastname: Tao
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Xue
authors.initials: X
authors.lastname: Shui
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Bo
authors.initials: B
authors.lastname: Ying
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Dongyu
authors.initials: D
authors.lastname: Chen
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Purva
authors.initials: P
authors.lastname: Pandya
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Edmond
authors.initials: E
authors.lastname: Chipumuro
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Zakir
authors.initials: Z
authors.lastname: Siddiquee
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Kevin
authors.initials: K
authors.lastname: Craig
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Chengjung
authors.initials: C
authors.lastname: Lai
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Henryk
authors.initials: H
authors.lastname: Dudek
authors.affiliation: University of Pittsburgh Medical Center, Pittsburgh, Pittsburgh.
authors.forename: Satdarshan P
authors.initials: SP
authors.lastname: Monga
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Bob D
authors.initials: BD
authors.lastname: Brown
authors.affiliation: Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Abrams
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D013329:Structure-Activity Relationship; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D034741:RNA, Small Interfering; D051176:beta Catenin; D018631:ras Proteins