Repositioning Bazedoxifene as a novel IL-6/GP130 inhibitor for sarcoma therapy

Research Inst Nationwide Children'S Hosp, Columbus OH

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Abstract

? DESCRIPTION (provided by applicant): Rhabdomyosarcoma is the most common childhood soft tissue sarcomas. No effective therapy exists for the 30-40% of patients that fail therapy or present with metastatic disease and no improvements in this outcome have occurred for over 15 years. Hence, there is a need for new therapeutic strategies for the rhabdomyosarcoma. It has been shown that IL-6 signaling plays an important role in cancer cell survival and progression. IL-6 binds to IL-6 R? to form a binary complex, then recruits GP130 to form the IL-6/IL-6 R?/GP130 heterotrimer and triggers a signaling cascade downstream. In the current study, we have presented evidence that IL-6 levels are elevated in primary tumors of rhabdomyosarcoma and human rhabdomyosarcoma cell lines. Therefore, IL-6 signaling presents a viable new target for rhabdomyosarcoma therapy. To date, however, no small molecules that target IL-6/GP130 signaling are available for cancer therapy in clinical trials. To speed up the IL-6/GP130 drug development, we have utilized a novel drug discovery approach combining Multiple Ligand Simultaneous Docking and drug repositioning to target GP130. Using this novel method, we have identified a FDA-approved drug Bazedoxifene [marketed as DUAVEE (Bazedoxifene with conjugated estrogens) by Pfizer for the prevention and treatment of postmenopausal osteoporosis] with a novel function to inhibit IL-6 and GP130 protein-protein interactions. The objective of this proposal is to further characterize the biologic activity of Bazedoxifene in rhabdomyosarcoma cells in vitro and test their inhibitory activity against IL-6/GP130 signaling in mice. Our long-term objective is to translate Bazedoxifene through clinical evaluation in patients with rhabdomyosarcoma with the ultimate goal of improving the clinical outcome for rhabdomyosarcoma and extending the quality of healthy life for people in this country. The following specific aims will be studied: Aim 1. Characterize the inhibitory effects and mechanisms of target inhibition of the Bazedoxifene in rhabdomyosarcoma cells. Aim 2. Evaluate the biologic activity of IL-6/GP130 pathway inhibition by Bazedoxifene on rhabdomyosarcoma cells in mouse tumor model in vivo.