Mechanisms of Herceptin resistance

赫赛汀耐药机制

基本信息

批准号：
8841327
负责人：
Lily Yang
金额：
$ 32.19万
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841327
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 Metastatic breast cancer 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.