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：
8996140
负责人：
Jiayuh Lin
金额：
$ 4.16万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8996140
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.

描述（适用提供）：横纹肌肉瘤是最常见的儿童软组织肉瘤。对于30％至40％的患者，尚无有效的治疗疗法或患有转移性疾病的患者，并且在15年以上没有改善这种结果。因此，需要为横纹肌肉瘤制定新的治疗策略。已经表明，IL-6信号传导在癌细胞存活和进展中起重要作用。 IL-6与IL-6R结合以形成二进制复合物，然后募集GP130形成IL-6/IL-6R/GP130杂三聚体，并触发下游的信号级联。在当前的研究中，我们提出了证据表明，在横纹肌肉瘤和人横纹肌肉瘤细胞系中，IL-6水平升高。因此，IL-6信号传导为横纹肌肉瘤治疗提供了可行的新目标。然而，迄今为止，靶向IL-6/GP130信号的小分子在临床试验中可用于癌症治疗。为了加快IL-6/GP130药物开发的速度，我们采用了一种新型的药物发现方法，该方法将多种配体同时停靠和药物重新定位与靶向GP130相结合。使用这种新颖的方法，我们已经确定了由辉瑞（Pfizer）预防和治疗绝经后骨质疏松症的FDA批准的药物Bazedoxifene（以Duavee（带有共轭进化的Bazedoxifene）销售）具有新功能，可抑制IL-6和GP130蛋白质蛋白质的相互作用。该建议的目的是进一步表征横纹肌肉瘤细胞中Bazedifene的生物学活性，并测试其对小鼠中IL-6/GP130信号传导的抑制活性。我们的长期目标是通过横纹肌肉瘤患者的临床评估来翻译Bazedoxifene，其最终目标是改善横纹肌肉瘤的临床结果，并扩大该国人的健康生活质量。将研究以下特定目的：目标1。表征横纹肌肉瘤细胞中Bazedoxifene的靶标抑制作用的抑制作用和机制。 AIM 2。评估BazEdifene在体内小鼠肿瘤模型中Bazedifene抑制IL-6/GP130途径的生物学活性。