Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

• DOI: 10.1073/pnas.1120068109
• Publication Date: 2012-07-03T02:45:15Z
• Authors: Austin Gurney; Fumiko Axelrod; Christopher J. Bond; Jennifer Cain; Cecile Chartier; Lucas Donigan; Marcus Fischer; Aurélie Chaudhari; May Ji; Ann M. Kapoun; Andrew Lam; Sasha Lazetic; Shirley Ma; Satyajit Mitra; In-Kyung Park; Kellie Pickell; Aaron Sato; Sanjeev Satyal; Michelle Stroud; Hoang Tran; Wan-Ching Yen; John Lewicki; Timothy Hoey
• Keywords: 0301 basic medicine; Blotting, Western; Genetic Vectors; Lentivirus; Antibodies, Monoclonal; Antineoplastic Agents; Drug Synergism; CHO Cells; Immunohistochemistry; Frizzled Receptors; 3. Good health; Immunoglobulin Fab Fragments; 03 medical and health sciences; Cricetulus; HEK293 Cells; Peptide Library; Cricetinae; Neoplasms; Animals; Humans; Luciferases; Wnt Signaling Pathway

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.