Targeting EphA2 in Glioblastoma

胶质母细胞瘤中的靶向 EphA2

基本信息

批准号：
9128090
负责人：
Bingcheng Wang
金额：
$ 55.29万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2016-03-15 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128090
关键词：
Address Adrenergic Receptor Affect Affinity Agonist Biological Assay Blood - brain barrier anatomy Cells Clinical Complement Complex Development Disease Doxazosin EphA2 Receptor Ephrins Etiology Genetically Engineered Mouse Glioblastoma Glioma Gliomagenesis Goals Heterogeneity Human Hypertension Implant In Vitro Knockout Mice Lead Ligand Binding Domain Ligands Malignant - descriptor Mesenchymal Modeling Molecular Mus Neoplasm Metastasis Oncogenic Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phosphoproteins Phosphorylation Phosphotransferases Pre-Clinical Model Preclinical Testing Property Proteins Radiation Radiation therapy Regulation Reporting Roentgen Rays Role Series Serine Signal Transduction Somatic Gene Therapy Stem cells Structure Survival Rate Testing Therapeutic Agents Therapeutic Intervention Translating Treatment Efficacy Tumor Cell Invasion Tumor Suppressor Proteins Xenograft procedure base cell motility chemotherapy design drug candidate functional restoration improved in vivo molecular subtypes mouse model neoplastic cell next generation novel novel therapeutics phosphoproteomics pre-clinical public health relevance relating to nervous system response screening small molecule stem stem cell differentiation targeted treatment temozolomide transcriptome sequencing tumor tumorigenesis virtual

项目摘要

DESCRIPTION (provided by applicant) Glioblastoma (GBM) remains a largely incurable disease, with a 5 year survival rate of less than 10%. Effective targeted therapies to complement already maximal radiation and chemotherapy are urgently needed. Converging evidence shows that the EphA2 receptor is an attractive target for GBM. The PI's lab and others recently uncovered dual roles of EphA2 in tumor etiology and malignant progression. When engaged with ligands (ephrin-As), EphA2 is a tumor suppressor and inhibits both ERK and Akt activities in GBM cells. However, in the absence of ligands, EphA2 is phosphorylated by AGC kinases including Akt and p90-RSK on serine 897, and S897 phosphorylation converts EphA2 from a tumor suppressor into an oncogenic protein that promotes glioma cell migration in vitro and intracranial invasion of glioma stem cells (GSC) in vivo. Moreover level of pS897-EphA2 is correlated with tumor grades. Mechanistically pS897- EphA2 regulates the stem properties of GSCs and promotes gliomagenesis in the absence of ligands. In contrast, upon ligand stimulation, EphA2 induces GSC differentiation and inhibits tumor development. Based on this series of observations, we propose that ligand-mimicking small molecule agonists of EphA2 can be novel therapeutic agents for GBM. Such agonists are expected to i) restore the intrinsic tumor suppressor functions of EphA2, ii) disrupt the pro- oncogenic Akt/RSK-EphA2 signaling axis, and iii) induce differentiation of GSCs. Using structure- guided virtual screening and cell-based assays, we reported that doxazosin (DZ), an α1- adrenoceptor antagonist still in clinical use for hypertension, is a bona fide EphA2 agonist. DZ inhibits ERK and Akt and suppresses tumor cell dissemination in an EphA2-dependent manner. Much more potent derivatives of DZ have been characterized through medicinal chemistry, including BW27, which suppressed GBM in preclinical models and was capable of crossing the blood-brain barrier (BBB). The overarching goal of this proposal is to translate these basic and preclinical discoveries into nove GBM therapeutic agents. BW27 will be subject to systemic preclinical test across all four molecular subtypes of human GBM. The on-target effects of BW27 will be investigated using the genetically engineered mouse model. Finally the X-ray co-crystal structure of EphA2 in complex with BW27 will be determined to guide the design of next generation(s) of EphA2 agonists. Completion of the studies could lead to new mechanism-based small molecule drug(s) for therapeutic intervention of GBM.

描述（由适用的）胶质母细胞瘤（GBM）仍然是一种无法治愈的疾病，5年的存活率低于10％。迫切需要有效的靶向疗法以完成最大的放射线和化学疗法。融合的证据表明，EPHA2受体是GBM的有吸引力目标。 PI的实验室和其他人最近发现了Epha2在肿瘤病因和恶性进展中的双重作用。当与配体（Ephrin-AS）互动时，Epha2是肿瘤抑制剂，并抑制GBM细胞中的ERK和AKT活性。 However, in the absence of ligands, EphA2 is phosphorylated by AGC kinases including Akt and p90-RSK on serine 897, and S897 phosphorylation converts EphA2 from a tumor suppressor into an oncogenic protein that promotes glioma cell migration in vitro and intracranial invasion of glioma stem cells (GSC) in vivo.此外，PS897-EPHA2的水平与肿瘤成绩相关。机械上的PS897-EPHA2调节GSC的茎特性，并在没有配体的情况下促进神经胶质作用。相反，在配体刺激下，EPHA2诱导GSC分化并抑制肿瘤的发展。基于这一系列的观察，我们提出，以Epha2的配体模拟小分子激动剂可以是GBM的新型治疗剂。预计此类激动剂会i）恢复以epha2的固有抑制函数，ii）破坏亲核的AKT/RSK-EPHA2信号轴，以及III）诱导GSC的分化。使用结构指导的虚拟筛查和基于细胞的测定，我们报告说，毒素（DZ）是一种仍在用于高血压临床用途的α1-肾上腺素受体拮抗剂，是一种真正的Epha2激动剂。 DZ抑制ERK和AKT并以Epha2依赖性方式抑制肿瘤细胞的传播。通过包括BW27在内的医学化学中，DZ的潜在衍生物具有更多的潜在衍生物，后者在临床前模型中抑制了GBM，并且能够越过血脑屏障（BBB）。该提案的总体目标是将这些基本和临床前的发现转化为Nove GBM治疗剂。 BW27将在人类GBM的所有四个分子亚型中进行全身性临床前测试。 BW27的目标效应将使用一般工程的鼠标模型进行研究。最后，将确定EPHA2与BW27复合物中的X射线共结晶结构，以指导Epha2激动剂的下一代设计。研究的完成可能会导致新的基于机制的小分子药物（S）用于GBM的治疗干预。