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

将巴多昔芬重新定位为用于肉瘤治疗的新型 IL-6/GP130 抑制剂

基本信息

批准号：
9291661
负责人：
Jiayuh Lin
金额：
$ 15.68万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9291661
关键词：
Academic Medical Centers Address Antitumor Response Apoptosis Binding Biochemical Biological Assay Cancer Patient Cell Line Cell Survival Cells Cellular Assay Child Childhood Rhabdomyosarcoma Childhood Soft Tissue Sarcoma Clinical Clinical Trials Complex Computer Simulation Conjugated Estrogens Country Data Development Disease Docking Drug Targeting Environment Future Generations Goals Hot Spot Human Immigration In Vitro Interleukin-6 Life Ligands Malignant Neoplasms Marketing Methods Modeling Molecular Mus Neoplasm Metastasis Ohio Outcome Pathway interactions Patients Pediatric Hospitals Pharmaceutical Preparations Phosphorylation Play Postmenopausal Osteoporosis Prevention Primary Neoplasm Proteins Proto-Oncogene Proteins c-akt Recruitment Activity Research Research Personnel Resources Rhabdomyosarcoma Role Safety Selective Estrogen Receptor Modulators Signal Transduction Soft tissue sarcoma Speed Stat3 protein Structure Survival Rate Testing Therapeutic Intervention Translating Tumor Suppression United States Food and Drug Administration base cancer cell cancer therapy disorder prevention drug development drug discovery effective therapy glycoprotein 130 human disease improved in vitro testing in vivo in vivo Model inhibitor/antagonist interleukin-6 receptor alpha mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics outcome forecast pediatric patients protein protein interaction public health relevance receptor research clinical testing sarcoma small molecule tumor tumor growth tumor xenograft

项目摘要

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.

横纹肌肉瘤是最常见的儿童软组织肉瘤。对于30-40%的治疗失败或存在转移性疾病的患者，没有有效的治疗方法，并且超过15年没有发生这种结局的改善。因此，横纹肌肉瘤需要新的治疗策略。研究表明，IL-6信号转导在癌细胞存活和进展中起重要作用。IL-6与IL-6 R β结合形成二元复合物，然后募集GP 130形成IL-6/IL-6 R β/GP 130异源三聚体并触发下游信号级联。在目前的研究中，我们提出的证据表明，在横纹肌肉瘤和人横纹肌肉瘤细胞系的原发性肿瘤中IL-6水平升高。因此，IL-6信号转导为横纹肌肉瘤的治疗提供了一个可行的新靶点。然而，迄今为止，没有靶向IL-6/GP 130信号传导的小分子可用于临床试验中的癌症治疗。为了加速IL-6/GP 130药物的开发，我们利用了一种新的药物发现方法，该方法结合了多配体同时对接和药物重新定位以靶向GP 130。使用这种新的方法，我们已经确定了FDA批准的药物Bazedoxifene [辉瑞公司以DUAVEE（Bazedoxifene与共轭雌激素）销售，用于预防和治疗绝经后骨质疏松症]，具有抑制IL-6和GP 130蛋白质-蛋白质相互作用的新功能。本提案的目的是进一步表征巴多昔芬在体外横纹肌肉瘤细胞中的生物活性，并测试其对小鼠中IL-6/GP 130信号传导的抑制活性。我们的长期目标是通过对横纹肌肉瘤患者的临床评价来转化Bazedoxifene，最终目标是改善横纹肌肉瘤的临床结局，并延长该国人民的健康生活质量。将研究以下具体目标：目标1。鉴定巴多昔芬在横纹肌肉瘤细胞中的抑制作用和靶向抑制机制。目标2.评价巴多昔芬抑制小鼠横纹肌肉瘤细胞IL-6/GP 130通路的生物学活性。