Repurposing the Selective Estrogen Receptor Modulator to Suppress Gastrointestinal Cancer Growth

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 utility of a steroid analog clinically approved for the treatment of osteoporosis, to suppress gp130-dependent tumor growth of the gastrointestinal epithelium. administration reduced gastric tumor burden in 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 and the associated β-catenin/canonical WNT pathway, treatment reduces tumor burden. Consistent with the proposed orthogonal tumor-promoting activity of IL11-dependent gp130/STAT3 signaling, tumors of -treated -mutant mice retain excessive nuclear accumulation of β-catenin and aberrant WNT pathway activation. Likewise, treatment of human colon cancer cells harboring mutant 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 for the treatment of gastrointestinal cancers in which IL11 plays a tumor-promoting role.