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Title: Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations.
Authors: Flanagan, Dustin J;Barker, Nick;Costanzo, Natasha S Di;Mason, Elizabeth A;Gurney, Austin;Meniel, Valerie S;Koushyar, Sarah;Austin, Chloe R;Ernst, Matthias;Pearson, Helen B;Boussioutas, Alex;Clevers, Hans;Phesse, Toby J;Vincan, Elizabeth
Affiliation: University of Melbourne, Department of Anatomy and Neuroscience, Melbourne, Victoria, Australia
Institute of Medical Biology, Singapore, Singapore
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
NTU School of Biological Sciences, Singapore, Singapore..
School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Australia
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia
University of Melbourne & Victorian Infectious Diseases Reference Laboratory, Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia
European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom..
OncoMed Pharmaceuticals Inc., Redwood City, California..
European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom..
Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, the Netherlands..
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Issue Date: 1-Mar-2019
EDate: 2019-01-08
Citation: Cancer research 2019; 79(5): 970-981
Abstract: A subset of patients with gastric cancer have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no in vivo studies investigating the potential of targeting Wnt receptors for treating gastric cancer, and the specific Wnt receptor transmitting oncogenic Wnt signaling in gastric cancer is unknown. Here, we use inhibitors of Wnt/Fzd (OMP-18R5/vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and ex vivo organoid cultures. Pharmacologic targeting of Fzd inhibited the growth of gastric adenomas in vivo. We identified Fzd7 to be the predominant Wnt receptor responsible for transmitting Wnt signaling in human gastric cancer cells and mouse models of gastric cancer, whereby Fzd7-deficient cells were retained in gastric adenomas but were unable to respond to Wnt signals and consequently failed to proliferate. Genetic deletion of Fzd7 or treatment with vantictumab was sufficient to inhibit the growth of gastric adenomas with or without mutations to Apc. Vantictumab is currently in phase Ib clinical trials for advanced pancreatic, lung, and breast cancer. Our data extend the scope of patients that may benefit from this therapeutic approach as we demonstrate that this drug will be effective in treating patients with gastric cancer regardless of APC mutation status. SIGNIFICANCE: The Wnt receptor Fzd7 plays an essential role in gastric tumorigenesis irrespective of Apc mutation status, therefore targeting Wnt/Fzd7 may be of therapeutic benefit to patients with gastric cancer.
DOI: 10.1158/0008-5472.CAN-18-2095
ORCID: 0000-0003-4351-0038
PubMed URL: 30622113
Type: Journal Article
Research Support, Non-U.S. Gov't
Appears in Collections:Journal articles

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