Abstract 186: FDA approved drug Bazedoxifene as a novel inhibitor of IL 6 and IL 11/GP130 signaling for osteosarcoma therapy
Authors: Wu Xiaojuan , Xiao Hui , Li Chenglong , Lin Jiayuh 
Published: July 2017

Abstract
IL-6 and L-11 signaling pathways play an important role in cancer cell survival and progression, including osteosarcoma. IL-6/IL-11 binds to IL-6/IL-11 Rα to form a binary complex, then recruits GP130 to form the IL-6/IL-6 Rα/GP130 or IL-11/IL-11 Rα/GP130 heterotrimer and triggers a signaling cascade downstream. One of the major downstream effectors of IL-6 is STAT3. STAT3 is persistently activated in many human osteosarcoma specimens and cell lines and STAT3 is required for osteosarcoma cells survival. So IL-6 and IL-11 present a viable novel target for osteosarcoma therapy. To date, however, no small molecules that target both IL-6/GP130 and IL-11/GP130 signaling pathways are available for cancer therapy. To overcome this critical problem, we have utilized a novel drug discovery approach combining Multiple Ligand Simultaneous Docking and drug repositioning to target GP130. Drug repositioning refers to reuse fragments from the existing FDA-approved drugs for new applications and could potentially reposition the existing drugs as novel, off-target inhibitors of the GP130 as their new target. Using this novel method, we have identified a FDA-approved drug Bazedoxifene with a novel function to inhibit IL-6 and GP130 proteinprotein interactions. Furthmore, because IL-11 binds to the same domain of GP130 as IL-6, Bazedoxifene should also inhibit IL-11/GP130 signaling. Accordingly, Bazedoxifene can indeed inhibit the induction of P-STAT3 by both IL-6 and IL-11. Bazedoxifene appeared specific to IL-6 and IL-11 as phosphorylation of STAT1 and STAT3 by IFN-γ and LIF respectively were not affected by the compound. Bazedoxifene inhibited P-STAT3 and induced apoptosis in human osteosarcoma cell lines expressing IL-6 and IL-11. In addition, Bazedoxifene can inhibit colony formation after the drug treatments in cancer cells.IL-6 but not IFN-γ could rescue the Bazedoxifene-mediated inhibition of cell viability in osteosarcoma cells. These results further support that IL-6/GP130 signaling pathway is one of the main targets of Bazedoxifene-mediated inhibition in osteosarcoma cells. To determine the in vivo activity of Bazedoxifene, we further tested the efficacy of Bazedoxifene in tumor xenografts generated from the SJSA osteosarcoma cells that show persistent IL-6/STAT3 activation. Bazedoxifene via oral gavage inhibited P-STAT3 and the growth of SJSA tumor xenografts. These data demonstrated that Bazedoxifene is potent in suppressing tumor growth and is orally bioavailable in inhibiting P-STAT3. It further indicates that Bazedoxifene is a promising IL-6/GP130-targeting drug, which likely to have in vivo anti-tumor activity in osteosarcoma. In summary, Bazedoxifene already approved for safety by the FDA as a novel inhibitor of IL-6/GP130 and IL-11/GP130 signaling should provide an easier path to clinical trials and have a potential to improve the outcome of osteosarcoma.
Note: This abstract was not presented at the meeting.
Citation Format: Xiaojuan Wu, Hui Xiao, Chenglong Li, Jiayuh Lin. FDA approved drug Bazedoxifene as a novel inhibitor of IL 6 and IL 11/GP130 signaling for osteosarcoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 186. doi:10.1158/1538-7445.AM2017-186