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

Abstract

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.differentiation | cancer stem cell | pancreatic | breast | lung

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

“…Examples include anti-LRP6 antibodies (18), and the anti-Frizzled antibody vantictumab (OMP-18R5; ref. 19). Vantictumab binds to 5 of the 10 Fzd receptors recognizing an epitope spanning the "cleft" region of Fzd that contains highly conserved residues (19,20).…”

“…19). Vantictumab binds to 5 of the 10 Fzd receptors recognizing an epitope spanning the "cleft" region of Fzd that contains highly conserved residues (19,20). Vantictumab may effectively target a subset of cancers that are dependent on the function of the appropriate Fzds.…”

“…There are also subsets of ovarian (25%), prostate (10%), and breast (10%) cancers with R-spondin2 gene amplifications. The tumors with elevated expression of RSPO either due to translocations or due to amplifications could also potentially respond to PORCN inhibitors, anti-Fzd antibodies, or anti-RSPO antibodies (19,25). Thus, RSPO2/3 gain-of-function mutations, together with RNF43/ZNRF3 loss-of-function mutations, molecularly define a population of patients with pathologically increased cellular sensitivity to Wnts, who may benefit from new upstream Wnt inhibitors.…”

Cancer Stem Cells and Response to Therapy

“…Another group showed indomethacin and aspirin induced reduced expression of β-catenin/TCF responsive genes, with no significant effect on nuclear localization of β-catenin (Dihlmann et al, 2001). In another study, it was shown a monoclonal antibody against frizzled receptor, OMP-18R5, inhibited tumor growth in xenograft models of several human tumors including pancreatic, breast, and lung cancer and decreased tumor-initiating cell frequency (Gurney et al, 2012). Table 2 summarizes a list of inhibitors of self-renewal pathways, some of which are already used in the clinic.…”

Review of the Molecular Pathogenesis of Osteosarcoma

“…The second class including the Dkk family exerts inhibition by endocytosis of co-receptors LRP5/6 (Kawano et al, 2003). Several Wnt antagonists, including Frzb/sFRP3 and Dkk-3, function as tumor suppressors (Zi et al, 2005;Guo et al, 2008;Abarzua et al, 2005;Rubin et al, 2010;Gurney et al, 2012). WIF-1 is a unique Wnt antagonist, structurally distinct from sFRP and Dkk families, which contains a WIF domain for Wnt binding activity and epidermal growth factor (EGF) repeats (Hsieh et al, 1999).…”