Poster Presentation 32nd Lorne Cancer 2020

Targeting gp130-dependent cytokine signalling in gastrointestinal cancers (#135)

Ashwini Chand 1 2 , Matthias Ernst 1 2 , Michael Parker 3 , Tracy Nero 3 , Pathum Thilakasiri 1
  1. Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia
  2. School of Cancer Medicine, Latrobe University, Melbourne, VIC, Australia
  3. Bio21 Institute, University of Melbourne, Melbourne, VIC, Australia

Excessive signaling through gp130, the shared receptor for the interleukin (IL)6 family of cytokines, is a common hallmark in solid malignancies and promotes their progression. Our work demonstrates the therapeutic utility of bazedoxifene, clinically approved for the treatment of osteoporosis, to suppress gp130‐dependent tumour growth of the gastrointestinal epithelium. Bazedoxifene administration reduced gastric tumour burden in gp130Y757F mice, where tumours arise exclusively through excessive gp130/STAT3 signaling in response to the IL6 family cytokine IL11. Likewise, in mouse models of sporadic colon and intestinal cancers, which arise from oncogenic mutations in the tumour suppressor gene Apc and the associated β‐catenin/canonical WNT pathway, bazedoxifene treatment reduces tumour burden. Consistent with the proposed orthogonal tumour‐promoting activity of IL11‐dependent gp130/STAT3 signaling, tumours of bazedoxifene‐treated Apc‐mutant mice retain excessive nuclear accumulation of β‐catenin and aberrant WNT pathway activation. Likewise, bazedoxifene treatment of human colon cancer cells harboring mutant APC did not reduce aberrant canonical WNT signaling, but suppressed IL11‐dependent STAT3 signaling. Our findings provide compelling proof of concept to support the repurposing of bazedoxifene for the treatment of gastrointestinal cancers in which IL11 plays a tumour‐promoting role.