Mechanisms of Herceptin resistance

赫赛汀耐药机制

基本信息

批准号：
9034335
负责人：
Lily Yang
金额：
$ 5.45万
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/9034335
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.

描述（由申请人提供）：HER2基因在大约30％的转移性乳腺癌中过表达，并且与疾病快速进展和总体生存率降低有关。对HER2靶向药物赫赛汀的反应持续时间不到一年，这表明获得的药物耐药性是治疗HER2过表达转移性乳腺癌的主要临床问题。该应用的长期目标是识别赫赛汀抵抗的机制和预测因子，以改善HER2过表达乳腺癌的患者的存活率。抗赫替素的细胞表达了细胞周期蛋白依赖性激酶（CDK）抑制剂P27的水平，并在胰岛素样生长因子-I受体（IGF-IR），HER2和HER3之间显示出独特的受体串扰。我们的中心假设是，IGF-IR/HER2/HER3复合物激活了下游激酶信号传导途径，促进p27的磷酸化和降解，从而导致HER2过表达乳腺癌细胞的增殖增加。 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到赫斯汀。访问获得的多种获得的Herceptin耐药性和多个患者肿瘤组织的途径使我们处于独特的位置，以发现新颖的治疗靶标和抗性标记。最终，这项研究将通过确定新的分子靶标，新型药物组合和耐药性乳腺癌的耐药性标记来使人类健康受益。了解导致获得赫斯蒂蛋白耐药性的机制最终会导致精致的治疗策略，并提高乳腺癌患者的存活率。