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

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

doi:10.15252/emmm.201809539

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.

Highlights

The contribution of inflammatory cytokines to the progression and treatment resistance of solid cancers is widely accepted, even for malignancies that occur in the absence of overt inflammation (Putoczki et al, 2013)
We identify interference with IL11 binding to the gp130 receptor signaling subunit as the mechanism by which bazedoxifene suppresses tumor growth in male and females hosts and on cells lacking ERa expression
Akin to our observations that inhibition of gp130 signaling at the level of ligand binding, engagement of the gp130-receptor-associated JAK kinases or activation of the STAT3 signal transducer suppresses tumor formation in gp130Y757F, Lgr5CreERT2; Apcflox and Cdx2CreERT2; Apcflox mice; bazedoxifene treatment replicated these effects

Summary

Introduction

The contribution of inflammatory cytokines to the progression and treatment resistance of solid cancers is widely accepted, even for malignancies that occur in the absence of overt inflammation (Putoczki et al, 2013). Among the cytokines most prominently involved in this process are those of the interleukin (IL)6/11 family, characterized by the shared use of the transmembrane receptor bsubunit gp130 (Ernst & Putoczki, 2012; Putoczki et al, 2013). We have recently identified a hitherto unrecognized tumor-promoting role for IL11 in mouse models of gastrointestinal cancers that arise in the mucosal epithelium of the stomach, small intestine, or colon (Ernst et al, 2008; Putoczki et al, 2013). Genetic restriction of IL11 signaling by either ablation of the IL11Ra co-receptor subunit, or therapeutic administration of the antagonistic “IL11Mutein” variant, limits the growth of tumors driven by excessive signaling of the canonical WNT pathway resulting from oncogenic b-catenin/CTBNN1 or APC mutations that underpin 80% of human colon cancer (Putoczki et al, 2013). We proposed that tumors exploit the IL6/11 family cytokines, which a 2019 The Authors.

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