Targeting Endocytic Recycling of EGF Receptor in Cancer

靶向癌症中 EGF 受体的内吞再循环

基本信息

批准号：
8788739
负责人：
Hamid Band
金额：
$ 4.62万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788739
关键词：
ATP phosphohydrolase Accounting Address Animal Model Animals Antibodies Antineoplastic Agents Apoptosis Architecture Attenuated Autoimmunity Back Behavior Binding Biochemical Biological Breast Breast Cancer Cell C-terminal Cancerous Cell Culture Techniques Cell Proliferation Cell surface Cells Cellular biology Complex Development Diabetes Mellitus Dimerization Disease Effectiveness Endocytosis Endosomes Epidermal Growth Factor Receptor Epithelial Equilibrium ErbB Receptor Family Protein Event Experimental Models Family Fc Receptor Funding Future Genes Genetic Health Homeostasis Homo Human Hyperactive behavior In Vitro Knockout Mice Laboratories Laboratory Study Lead Learning Ligand Binding Ligands Link Lung Lysosomes Maintenance Malignant Neoplasms Mediating Modality Molecular Mus Mutation Normal Cell Nucleotides Oncogenic Output Pathway interactions Patients Pharmaceutical Preparations Physiological Play Preventive Process Protein Family Protein Tyrosine Kinase Proteins Radiation Reagent Receptor Activation Receptor Protein-Tyrosine Kinases Recycling Regulation Research Design Resistance development Role Route Signal Transduction Sorting - Cell Movement Structure Surface System Testing Therapeutic Tissues Ubiquitination Work Xenograft procedure anti-cancer therapeutic base cancer therapy chemotherapeutic agent chemotherapy design drug development in vivo insight kinase inhibitor malignant breast neoplasm member migration mouse model new therapeutic target novel novel strategies overexpression receptor receptor function response small molecule therapeutic target trafficking tumor progression tumorigenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): EGF receptor and other members of the ErbB family of receptor tyrosine kinases (RTKs) play essential physiological roles in development and maintenance of epithelial tissues by generating cell proliferation, survival, differentiation, and migration signals in response to specific ligands. Activation of ErbB receptors is also linked to the initiation and progression of human cancers. These RTKs have emerged as important therapeutic targets of anti-receptor antibodies and kinase inhibitors, although both therapeutic modalities suffer from rapid resistance development, necessitating alternate approaches to ErbB-targeted therapy. An essential pre-requisite for cellular response to EGFR and other RTK ligands is that an activation-competent pool of RTKs must be displayed on the cell surface. ErbB receptor overexpression increases this activation-ready pool. Sufficiently high levels of ErbB receptor overexpression induce ligand-independent activation, which can also be achieved by cancer-associated activating mutations. A fundamental feature of RTK function is that the newly synthesized as well as ligand-internalized receptors undergo a sorting process that determines whether they will recycle back to the cell surface for ligand binding and signaling or will be targeted for lysosomal degradation. We, and others, have shown that Cbl family of ubiquitin ligases are essential regulators of the lysosomal fate. Studies carried out by others and by us during the current funding period have led to a novel hypothesis that members of the C-terminal Eps15-homology (EH) domain-containing (EHD) protein family function as key regulators of the recycling fate of receptors. In this competing renewal application, we will employ unique EHD knockout mouse models and cellular reagents derived from these animals together with a vast array of immunological, biochemical and cellular reagents that have been generated to test the hypotheses: EHD protein-dependent endocytic recycling is a key controller of the cell surface display and recycling fate of EGFR; loss of EHD function will attenuate the ability of EGFR to propagate oncogenic signals in vitro and will abrogate EGFR-driven oncogenesis in vivo; and abrogation of endocytic recycling will enhance the efficacy of EGFR targeted therapy with an inhibitory antibody. Thus, this proposal will evaluate the endocytic recycling of EGFR as a novel therapeutic target in EGFR-driven cancer. Insights gained from these studies should further our understanding of the molecular and cell biological regulators of oncogenic signaling by RTKs, and help validate the endocytic recycling of RTKs as a new approach to rationally design anti-cancer agents to potentiate existing RTK-targeted therapies.

描述（由申请人提供）：EGF 受体和受体酪氨酸激酶 (RTK) ErbB 家族的其他成员通过响应特定的细胞增殖、存活、分化和迁移信号，在上皮组织的发育和维持中发挥重要的生理作用。配体。 ErbB 受体的激活也与人类癌症的发生和进展有关。这些 RTK 已成为抗受体抗体和激酶抑制剂的重要治疗靶点，尽管这两种治疗方式都遭受快速耐药性发展，需要采用 ErbB 靶向治疗的替代方法。细胞对 EGFR 和其他 RTK 配体做出反应的一个重要先决条件是，必须在细胞表面展示具有激活能力的 RTK 库。 ErbB 受体过度表达增加了该激活准备池。足够高水平的 ErbB 受体过度表达会诱导配体独立的激活，这也可以通过癌症相关的激活突变来实现。 RTK 功能的一个基本特征是，新合成的以及配体内化的受体经历一个分选过程，该过程决定它们是否会再循环回细胞表面进行配体结合和信号传导，或者将被靶向溶酶体降解。我们和其他人已经证明，泛素连接酶的 Cbl 家族是溶酶体命运的重要调节因子。在当前资助期间，其他人和我们进行的研究得出了一个新的假设，即 C 端 Eps15 同源 (EH) 结构域 (EHD) 蛋白家族的成员作为受体循环命运的关键调节因子。在这一竞争性更新应用中，我们将采用独特的 EHD 敲除小鼠模型和源自这些动物的细胞试剂，以及已生成的大量免疫学、生化和细胞试剂来测试以下假设：EHD 蛋白依赖性内吞循环是一种细胞表面显示和EGFR回收命运的关键控制者； EHD功能的丧失将削弱EGFR在体外传播致癌信号的能力，并将消除EGFR驱动的体内肿瘤发生；废除内吞再循环将增强抑制性抗体的 EGFR 靶向治疗的功效。因此，该提案将评估 EGFR 的内吞再循环作为 EGFR 驱动的癌症的新治疗靶点。从这些研究中获得的见解应进一步加深我们对 RTK 致癌信号传导的分子和细胞生物调节因子的理解，并有助于验证 RTK 的内吞循环作为合理设计抗癌药物以增强现有 RTK 靶向疗法的新方法。

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）

EHD4 is a novel regulator of urinary water homeostasis.

EHD4 是一种新型的尿水稳态调节剂。

DOI：
10.1096/fj.201601182rr
发表时间：
2017
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Rahman,ShammaS;Moffitt,AlexandraEJ;Trease,AndrewJ;Foster,KirkW;Storck,MatthewD;Band,Hamid;Boesen,ErikaI
通讯作者：
Boesen,ErikaI