Poster Presentation 29th Lorne Cancer Conference 2017

Targeting Frizzled receptors in gastric cancer (#158)

Dustin Flanagan 1 2 , Nick Barker 3 , Austin Gurney 4 , Hans Clevers 5 , Matthias Ernst 6 , Toby Phesse 7 , Elizabeth Vincan 1 2
  1. The University of Melbourne, Melbourne, Australia
  2. Victorian Infectious Disease Reference Laboratory, Melbourne, Australia
  3. Institute of Medical Biology (A'STAR), Singapore
  4. OncoMed Pharmaceuticals, Redwood City, USA
  5. Hubrecht Institute, Utrecht, Netherlands
  6. Olivia Newton-John Cancer Research Institute, Melbourne, Australia
  7. European Cancer Stem Cell Research Institute, Cardiff, UK

Gastric cancer is the fourth most common cancer globally and the second most common cause of death with a poor 5-year survival rate due to late stage of diagnosis. Gastric cancer can be divided pathologically into two broad groups, intestinal-type and diffuse-type, as classified by the Lauren system. Of the reported mutations in gastric cancer, multiple components of the Wnt pathway receptor complex (Frizzled (Fzd) receptors, E3 ligases and pathway antagonists) are commonly mutated/modified in intestinal-type gastric cancer, leading to aberrant activation of Wnt signaling. As such, targeting the Wnt receptor complex may provide potential therapeutic benefit in models of intestinal-type gastric cancer. We sought to determine the function and therapeutic benefit of targeting Frizzled receptors in both in vivo and in vitro models of gastric cancer.

Pilot experiments used a pan Fzd-blocking antibody (OMP18R5) to treat a well characterised mouse model of gastric cancer, gp130F/Fwhich display elevated Wnt pathway activation. gp130F/F mice treated for 30 days with OMP18R5 showed a significant decrease in tumour burden compared to vehicle treated controls. Accompanying reduced tumourigenesis, OMP18R5 treated animals showed significant reductions in cell proliferation, angiogenesis and Wnt target gene expression. Differential gene expression analysis in vehicle treated gp130F/F mice identified Fzd7 to be significantly upregulated compared to other Fzd receptors, which was subsequently reduced in expression following treatment with OMP18R5. As such, we used a novel transgenic mouse to conditionally delete Fzd7 from gp130F/F tumours. Successful deletion of Fzd7 from gp130F/F mice phenocopied the reduction in tumour burden observed in OMP18R5 treated gp130F/F mice, demonstrating that Fzd7 is a key receptor responsible for transducing Wnt signals to gp130F/F tumours. These findings were further extended using human intestinal-type gastric cancer cell lines and ex-vivo organoids derived from gp130F/F mice, demonstrating targeted inhibition of Fzd7 reduced elevated Wnt pathway activation, target gene expression, cell viability and clonogenicity. Collectively, these data demonstrate that genetic or pharmacological targeting of Fzd receptors is rate-limiting for intestinal-type gastric tumourigenesis and thus could be used in combination with other standard cancer therapies in the clinic to treat gastric cancer patients.