Abstract 4962: Repurposing bazedoxifene to suppress gastrointestinal cancer growth

Abstract

Abstract The interleukin (IL)6 family of inflammatory cytokines, characterized by the shared use of the gp130 receptor, supports the progression of solid cancers. Specifically, gp130 signaling becomes rate limiting for the growth of gastrointestinal tumors arising from oncogenic driver mutations in Apc, but remains dispensable for the homeostatic renewal of the gastrointestinal mucosa. In the present study we investigate the effects of the selective estrogen receptor modulator bazedoxifene, clinically approved for the treatment of osteoporosis, as a putative small molecule inhibitor of gp130 receptor oligomerization and activation. We assessed the effects of bazedoxifene on IL6 and IL11-dependent STAT3 activation and cell proliferation in gastric and colon cancer cell lines. In patient-derived colon cancer organoid cultures, we assessed bazedoxifene effects on IL11-dependent growth. The gp130Y757F, Lgr5CreERT2- or Cdx2CreERT2-driven Apc flox mouse models of gastrointestinal cancer, were used to examine the effects of bazedoxifene on tumour growth. In silico modeling suggests that the inhibitory activity of bazedoxifene is due to its ability to mimic the interaction between the Site III interface of gp130 receptor and the tryptophan-157 in IL6, or tryptophan-168 in IL11 cytokine. We show that bazedoxifene interferes with IL6 and IL11-dependent proliferation of BAF/03 cells. Bazedoxifene suppresses gastric tumor growth in gp130Y757F mice irrespective of their gender, in which tumors arise through excessive IL11-dependent STAT3 signaling. Strikingly, in sporadic colon cancer models based on aberrant activation of the β-catenin/canonical WNT pathway, bazedoxifene treatment also reduces tumor burden in mice following conditional ablation of the Apc suppressor gene using the Lgr5CreERT2- or Cdx2CreERT2-driver alleles. Consistent with our observation that nuclear accumulation of β-catenin remains unaffected in colonic tumors of bazedoxifene-treated mice, bazedoxifenetreatment of human SW480 colon cancer cells harboring mutant APC did not affect canonical WNT signaling, but suppressed IL11-dependent STAT3 signaling. Our findings provide compelling proof-of-concept for the repurposing of bazedoxifene for the treatment of gastrointestinal cancers that arise from bona fide oncogenic driver mutations. Note: This abstract was not presented at the meeting. Citation Format: Pathum Thilakasiri, Tracy Nero, Michael W. Parker, Matthias Ernst, Ashwini L. Chand. Repurposing bazedoxifene to suppress gastrointestinal cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4962.