Open AccessWnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors
Author(s) -
Austin Gurney,
Fumiko Axelrod,
Christopher J. Bond,
Jennifer Cain,
Cécile Chartier,
Lucas Donigan,
Marcus Fischer,
Aurélie Chaudhari,
May Ji,
Ann M. Kapoun,
Andrew Lam,
Sasha Lazetic,
Shirley Ma,
Satyajit K. Mitra,
Inkyung Park,
Kellie Pickell,
Aaron K. Sato,
Sanjeev Satyal,
Michelle Stroud,
Hoang Tran,
Wan-Ching Yen,
John Lewicki,
Timothy Hoey
Publication year - 2012
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1120068109
Subject(s) - frizzled , wnt signaling pathway , lrp6 , receptor , monoclonal antibody , epitope , lrp5 , cancer research , biology , antibody , signal transduction , wnt3a , microbiology and biotechnology , extracellular , immunology , genetics
The Wnt/β-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting the Wnt pathway with a monoclonal antibody, OMP-18R5. This antibody, initially identified by binding to Frizzled 7, interacts with five Fzd receptors through a conserved epitope within the extracellular domain and blocks canonical Wnt signaling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, this antibody inhibits the growth of a range of tumor types, reduces tumor-initiating cell frequency, and exhibits synergistic activity with standard-of-care chemotherapeutic agents.
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