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

Pathum Thilakasiri; Jennifer Huynh; Ashleigh R Poh; Chin Wee Tan; Tracy L Nero; Kelly Tran; Adam C Parslow; Shoukat Afshar-Sterle; David Baloyan; Natalie J Hannan; Michael Buchert; Andrew Mark Scott; Michael Dw Griffin; Frederic Hollande; Michael W Parker; Tracy L Putoczki; Matthias Ernst; Ashwini L Chand

Journal article

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

Pathum Thilakasiri, Jennifer Huynh, Ashleigh R Poh, Chin Wee Tan, Tracy L Nero, Kelly Tran, Adam C Parslow, Shoukat Afshar-Sterle, David Baloyan, Natalie J Hannan, Michael Buchert, Andrew Mark Scott, Michael Dw Griffin, Frederic Hollande, Michael W Parker, Tracy L Putoczki, Matthias Ernst, Ashwini L Chand

EMBO Molecular Medicine | EMBO Press | Published : 2019

DOI: 10.15252/emmm.201809539

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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 gp130Y757F 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 suppr..

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University of Melbourne Researchers

Chin Tan Author

Tracy Nero Author

Natalie Hannan Author

Andrew Scott Author

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Grants

Awarded by Cure Brain Cancer Foundation

Funding Acknowledgements

We acknowledge the support of the Victorian State Government Operational Infrastructure Support and the National Medical Health and Research Council (NHMRC) of Australia. The authors acknowledge funding support from NHMRC, Cancer Australia, Ludwig Cancer Research, John T Reid Trusts, Cure Brain Cancer Foundation, Cancer Council Victoria, and the Victoria Cancer Agency. The authors acknowledge NHMRC Fellowship support to A.L.C (1062247), M.W.P (1117183), and M.E (1079257), and Australian Research Council Future Fellowship support to M.D.W.G (FT140100544). Authors also acknowledge grant funding from NHMRC to F.H (1069024) and M.E (1092788). We are grateful to Prof Nicola (WEHI) for the kind donation of BAF/03IL6Ra and BAF/03LIFR cells for use in experiments.