Mechanisms of Herceptin resistance

赫赛汀耐药机制

基本信息

批准号：
8810741
负责人：
RITA NAHTA
金额：
$ 2.85万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-07 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8810741
关键词：
ALPP Animal Model Breast Cancer Cell Breast Cancer Treatment Cell Cycle Arrest Cells Clinical Complex Data Disease Progression Docking Down-Regulation Drug Combinations Drug Targeting Drug resistance ERBB2 gene ERBB3 gene Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Genes Genetic Goals Health Human Insulin-Like-Growth Factor I Receptor Lead Mediating Modeling Molecular Target Mouse Mammary Tumor Virus Nanotechnology Oncologist PIK3CG gene PTK2 gene Pathologist Patients Pharmacology Phosphorylation Phosphorylation Site Phosphotransferases Positioning Attribute Receptor Cross-Talk Regulation Research Research Personnel Resistance Roche brand of trastuzumab Role Signal Pathway Signal Transduction Staining method Stains Survival Rate Therapeutic Transgenic Model Tumor Tissue Ubiquitin Ubiquitination animal tissue base cyclin-dependent kinase inhibitor 1B improved in vivo in vivo Model innovation interdisciplinary approach malignant breast neoplasm molecular marker nanomaterials new therapeutic target novel novel therapeutics overexpression receptor resistance mechanism response

项目摘要

DESCRIPTION (provided by applicant): The her2 gene is overexpressed in approximately 30% of metastatic breast cancers, and is associated with rapid disease progression and reduced overall survival. The median duration of response to the HER2-targeted drug Herceptin is less than one year, indicating that acquired drug resistance is a major clinical problem in the treatment of HER2-overexpressing metastatic breast cancer. The long-term goal of this application is to identify mechanisms and predictors of Herceptin resistance in order to improve the survival of patients with HER2-overexpressing breast cancer. Herceptin-resistant cells express reduced levels of the cyclin-dependent kinase (cdk) inhibitor p27 and show a unique receptor cross-talk between insulin-like growth factor-I receptor (IGF-IR), HER2, and HER3. Our central hypothesis is that the IGF-IR/HER2/HER3 complex activates downstream kinase signaling pathways that promote phosphorylation and degradation of p27, causing increased proliferation of HER2-overexpressing breast cancer cells. Using a particularly innovative multidisciplinary approach that combines nanotechnology, genetics, and pharmacology, we will determine (1) the mechanisms by which p27 is down- regulated in acquired Herceptin resistance, (2) the role of the IGF-IR/HER2/HER3 receptor complex in acquired Herceptin resistance, and (3) if IGF-IR, HER3, and FAK are in vivo targets for improving response to Herceptin. Access to multiple models of acquired Herceptin resistance and multiple patient tumor tissue sets places us in a unique position to discover novel therapeutic targets and markers of resistance. Ultimately, this study will benefit human health by identifying new molecular targets, novel drug combinations, and molecular markers of drug resistance in HER2-overexpressing breast cancer. Understanding the mechanisms leading to acquired Herceptin resistance will ultimately lead to refined therapeutic strategies and improved survival rates for patients with breast cancer.

描述（由申请人提供）：her2 基因在大约 30% 的转移性乳腺癌中过度表达，并且与疾病快速进展和总体生存率降低相关。 HER2靶向药物赫赛汀的中位反应持续时间不到一年，表明获得性耐药是治疗HER2过表达的转移性乳腺癌的一个主要临床问题。该应用的长期目标是确定赫赛汀耐药的机制和预测因子，以提高 HER2 过表达乳腺癌患者的生存率。赫赛汀耐药细胞的细胞周期蛋白依赖性激酶 (cdk) 抑制剂 p27 表达水平降低，并显示胰岛素样生长因子 I 受体 (IGF-IR)、HER2 和 HER3 之间独特的受体串扰。我们的中心假设是 IGF-IR/HER2/HER3 复合物激活下游激酶信号通路，促进 p27 磷酸化和降解，导致 HER2 过表达乳腺癌细胞增殖增加。使用结合纳米技术、遗传学和药理学的特别创新的多学科方法，我们将确定 (1) p27 在获得性赫赛汀耐药中下调的机制，(2) IGF-IR/HER2/HER3 受体的作用(3) IGF-IR、HER3 和 FAK 是否是改善赫赛汀反应的体内靶标。获得获得性赫赛汀耐药的多种模型和多种患者肿瘤组织集使我们处于发现新的治疗靶点和耐药标记物的独特地位。最终，这项研究将通过确定 HER2 过表达乳腺癌的新分子靶点、新药物组合和耐药性分子标志物，造福人类健康。了解导致获得性赫赛汀耐药的机制最终将有助于制定完善的治疗策略并提高乳腺癌患者的生存率。