ErbB2 Downregulation Through HSP90 Inhibition

通过 HSP90 抑制下调 ErbB2

基本信息

批准号：
7212882
负责人：
Hamid Band
金额：
$ 4.92万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2007-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7212882
关键词：
Animals Ansamycin Antineoplastic Antibiotic Antibodies Antineoplastic Agents Area Biochemical Bioinformatics Biological Biology Breast Breast Cancer Cell Cancer Etiology Cancer Patient Cancer cell line Cell Proliferation Cell surface Cells Clinical Clinical Research Dominant-Negative Mutation Down-Regulation ERBB2 gene Enzymes Epidermal Growth Factor Receptor Family Family member Geldanamycin Growth HSP 90 inhibition Heat-Shock Proteins 90 Her2/erbb2/neu Staining Method Heregulin Heterodimerization Human Knowledge Lead Ligands Lysosomes Malignant Neoplasms Mediating Modification Molecular Molecular Chaperones Mono-S Nude Mice Pathway interactions Patients Pharmaceutical Preparations Phase Play Polyubiquitin Process Protein Overexpression Protein Tyrosine Kinase Proteins Proteomics Public Health RNA Interference Recruitment Activity Recycling Relapse Relative (related person)Rifabutin Role Signal Transduction Signaling Protein Surface Testing Therapeutic Therapeutic Effect Translating Trastuzumab Ubiquitin Ubiquitination Variant Work Xenograft procedure Yeasts anticancer activity attenuation base hormone therapy human SGTA protein improved in vivo inhibitor/antagonist insight malignant breast neoplasm member multicatalytic endopeptidase complex novel novel therapeutics outcome forecast receptor response success therapeutic target trafficking tumor ubiquitin ligase ubiquitin-protein ligase yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Technical Description: ErbB2 (Her2/Neu) overexpression is found in 20-30% of breast cancer patients as well as other cancers, and signifies poor prognosis. Success with humanized anti-ErbB2 antibodies has further validated ErbB2 as a therapeutic target. Ansamycin HSP90 inhibitors, such as 17AAG, are in phase l/ll clinical studies as novel anticancer agents as they target ErbB2 and other signaling proteins for ubiquitin-dependent degradation. Based on recent studies by us and others, we hypothesize that CHIP (C-terminus of HSP70-lnteracting Protein) and additional hitherto unknown ubiquitin ligases mediate 17AAG-induced ErbB2 downregulation either through proteasomal or through lysosomal degradation. Here, we propose comprehensive strategies to test these hypotheses. We will carry out cell biological, molecular and biochemical studies to distinguish whether HSP90 inhibitor-driven ErbB2 downregulation is mediated through degradation in the proteasome, lysosome or both. We will examine the role of CHIP and several candidate proteins identified through bioinformatics in 17AAG-induced ErbB2 ubiquitinylation and degradation, proliferation and survival of ErbB2 overexpressing breast cancer cell lines and in their in vivo growth in nude mice, using overexpression, dominant-negative mutant expression and RNAi knockdown strategies. If additional unknown ubiquitin ligases appear likely to mediate 17AAG-induced ErbB2 degradation, we will employ proteomics and yeast two-hybrid approaches to identify these proteins and characterize them functionally as for CHIP and other candidates. Through this comprehensive approach, we hope to elucidate the biological basis of ErbB2 downregulation by HSP90 inhibitory drugs and their anticancer activity. Success of these studies will open new therapeutic avenues for ErbB2-driven cancers as well those caused by EGFRvlll, an ErbB1 variant with biological similarities with ErbB2. Relevance to Public Health: This proposal will investigate new means of interfering with a cancer-causing protein Her2/Neu that is highly increased in 20-30% breast cancers with worst prognosis. The proposed studies could provide a basis for newer, more effective targeted therapies against breast and other cancers.

描述（由申请人提供）：技术描述：ErbB2 (Her2/Neu) 过度表达存在于 20-30% 的乳腺癌患者以及其他癌症中，并且预示着不良预后。人源化抗 ErbB2 抗体的成功进一步验证了 ErbB2 作为治疗靶点。安莎霉素 HSP90 抑制剂（例如 17AAG）作为新型抗癌药物正处于 l/ll 期临床研究中，因为它们以 ErbB2 和其他信号蛋白为靶点进行泛素依赖性降解。根据我们和其他人最近的研究，我们假设 CHIP（HSP70 相互作用蛋白的 C 末端）和其他迄今为止未知的泛素连接酶通过蛋白酶体或溶酶体降解介导 17AAG 诱导的 ErbB2 下调。在这里，我们提出了综合策略来检验这些假设。我们将进行细胞生物学、分子和生化研究，以区分 HSP90 抑制剂驱动的 ErbB2 下调是否是通过蛋白酶体、溶酶体或两者的降解介导的。我们将使用过表达、显性失活突变体，研究 CHIP 和通过生物信息学鉴定的几种候选蛋白在 17AAG 诱导的 ErbB2 泛素化和 ErbB2 过表达乳腺癌细胞系的降解、增殖和存活及其在裸鼠体内生长中的作用。表达和 RNAi 敲低策略。如果其他未知的泛素连接酶似乎可能介导 17AAG 诱导的 ErbB2 降解，我们将采用蛋白质组学和酵母双杂交方法来鉴定这些蛋白质，并像 CHIP 和其他候选蛋白一样对它们进行功能表征。通过这种综合方法，我们希望阐明 HSP90 抑制药物下调 ErbB2 的生物学基础及其抗癌活性。这些研究的成功将为 ErbB2 驱动的癌症以及 EGFRvIII（一种与 ErbB2 具有生物学相似性的 ErbB1 变体）引起的癌症开辟新的治疗途径。与公共健康的相关性：该提案将研究干扰致癌蛋白 Her2/Neu 的新方法，这种蛋白在 20-30% 预后最差的乳腺癌中高度增加。拟议的研究可以为针对乳腺癌和其他癌症的更新、更有效的靶向疗法提供基础。