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:
- 金额:$ 15.68万
- 依托单位:
- 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:
- 关键词:Academic Medical CentersAddressAntitumor ResponseApoptosisBindingBiochemicalBiological AssayCancer PatientCell LineCell SurvivalCellsCellular AssayChildChildhood RhabdomyosarcomaChildhood Soft Tissue SarcomaClinicalClinical TrialsComplexComputer SimulationConjugated EstrogensCountryDataDevelopmentDiseaseDockingDrug TargetingEnvironmentFutureGenerationsGoalsHot SpotHumanImmigrationIn VitroInterleukin-6LifeLigandsMalignant NeoplasmsMarketingMethodsModelingMolecularMusNeoplasm MetastasisOhioOutcomePathway interactionsPatientsPediatric HospitalsPharmaceutical PreparationsPhosphorylationPlayPostmenopausal OsteoporosisPreventionPrimary NeoplasmProteinsProto-Oncogene Proteins c-aktRecruitment ActivityResearchResearch PersonnelResourcesRhabdomyosarcomaRoleSafetySelective Estrogen Receptor ModulatorsSignal TransductionSoft tissue sarcomaSpeedStat3 proteinStructureSurvival RateTestingTherapeutic InterventionTranslatingTumor SuppressionUnited States Food and Drug Administrationbasecancer cellcancer therapydisorder preventiondrug developmentdrug discoveryeffective therapyglycoprotein 130human diseaseimprovedin vitro testingin vivoin vivo Modelinhibitor/antagonistinterleukin-6 receptor alphamouse modelnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsoutcome forecastpediatric patientsprotein protein interactionpublic health relevancereceptorresearch clinical testingsarcomasmall moleculetumortumor growthtumor 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。目标二。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。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Repositioning Bazedoxifene as a novel IL-6/GP130 signaling antagonist for human rhabdomyosarcoma therapy.
- DOI:10.1371/journal.pone.0180297
- 发表时间:2017
- 期刊:
- 影响因子:3.7
- 作者:Xiao H;Bid HK;Chen X;Wu X;Wei J;Bian Y;Zhao C;Li H;Li C;Lin J
- 通讯作者:Lin J
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Jiayuh Lin其他文献
Jiayuh Lin的其他文献
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Co-Targeting IL-6 and CDK4/6 Pathways as a Novel Approach of Preventive Therapy for Triple-Negative Breast Cancer
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$ 15.68万 - 项目类别:
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
- 批准号:
8996140 - 财政年份:2015
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8516641 - 财政年份:2013
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A new curcumin analogue with potent suppressive activity in pancreatic cancer
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