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EMBO Mol Med. 2019 Apr;11(4). pii: e9539. doi: 10.15252/emmm.201809539.

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth.

Author information

1
Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, Vic., Australia.
2
The Walter and Eliza Hall Institute, Melbourne, Vic., Australia.
3
ACRF Rational Drug Discovery Centre, St Vincent's Institute, Melbourne, Vic., Australia.
4
Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, Vic., Australia.
5
Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Vic., Australia.
6
Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Vic., Australia.
7
Department of Medicine, University of Melbourne, Melbourne, Vic., Australia.
8
Department of Clinical Pathology, University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, University of Melbourne, Melbourne, Vic., Australia.
9
Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, Vic., Australia matthias.ernst@onjcri.org.au ashwini.chand@onjcri.org.au.

Abstract

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. Here, we established the in vivo utility of bazedoxifene, a steroid analog clinically approved for the treatment of osteoporosis, to suppress gp130-dependent tumor growth of the gastrointestinal epithelium. Bazedoxifene administration reduced gastric tumor burden in gp130 Y757F mice, where tumors 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 tumor suppressor gene Apc and the associated β-catenin/canonical WNT pathway, bazedoxifene treatment reduces tumor burden. Consistent with the proposed orthogonal tumor-promoting activity of IL11-dependent gp130/STAT3 signaling, tumors 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 tumor-promoting role.

KEYWORDS:

colon cancer; gastric cancer; gp130; interleukin‐11; interleukin‐6

PMID:
30885958
DOI:
10.15252/emmm.201809539
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