Journal Article

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

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

2019

Overview

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. Synopsis Inhibition of gp130‐receptor/STAT3 activity confers anti‐tumor effects in mouse models of gastrointestinal cancers. This effect is recapitulated in mice treated with bazedoxifene, an FDA‐approved drug for osteoporosis treatment, supporting its repurposing as treatment in gastrointestinal cancers. First proof‐of‐concept demonstration that bazedoxifene, an FDA‐approved drug for postmenopausal osteoporosis, inhibits the growth of gastric and colon cancers using three independent mouse models. Mechanistically, this arises from the capacity of bazedoxifene to systemically inhibit gp130/STAT3 signalling as demonstrated in the gp130Y757F mouse model of intestinal‐type gastric cancer. This data provides a strong rationale to support future clinical efforts for repurposing bazedoxifene as an inhibitor of gp130/STAT3 signaling. Graphical Abstract Inhibition of gp130‐receptor/STAT3 activity confers anti‐tumor effects in mouse models of gastrointestinal cancers. This effect is recapitulated in mice treated with bazedoxifene, an FDA‐approved drug for osteoporosis treatment, supporting its repurposing as treatment in gastrointestinal cancers.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Adenomatous polyposis coli / Adenomatous Polyposis Coli Protein - genetics / Animal models / Animals / beta Catenin - metabolism / Brain cancer / Catenin / Cell Proliferation - drug effects / Colon cancer / Colorectal cancer / Councils / Cytokine Receptor gp130 - chemistry / Cytokine Receptor gp130 - metabolism / Cytokines / Disease Models, Animal / Drug Repositioning / EMBO03 / EMBO12 / EMBO28 / Epithelium / Female / Gastric cancer / Gastrointestinal Neoplasms - drug therapy / Gastrointestinal Neoplasms - pathology / Glycoprotein gp130 / gp130 / Humans / Indoles - metabolism / Indoles - pharmacology / Indoles - therapeutic use / Inflammation / Interleukin 1 / Interleukin 11 / Interleukin 6 / Interleukin-11 - chemistry / Interleukin-11 - metabolism / Interleukin-11 - pharmacology / Intestine / Ligands / Male / Medical research / Mice / Mice, Inbred C57BL / Mice, Transgenic / Mutation / Osteoporosis / Proteins / Research Article / Selective Estrogen Receptor Modulators - metabolism / Selective Estrogen Receptor Modulators - pharmacology / Selective Estrogen Receptor Modulators - therapeutic use / Signal transduction / Signal Transduction - drug effects / Small intestine / Stat3 protein / STAT3 Transcription Factor - metabolism / Tumor suppressor genes / Tumors / Wnt protein / Xenograft Model Antitumor Assays