Molecular determinants underlying herceptin sensitivity and resistance

赫赛汀敏感性和耐药性的分子决定因素

基本信息

批准号：
8737478
负责人：
XIAO-FAN WANG
金额：
$ 17.07万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737478
关键词：
Accounting Adjuvant Therapy Binding Biological Biological Assay Biological Process Breast Cancer Cell Cancer Patient Cell Aging Cell Cycle Cell Cycle Arrest Cell Line Cell Proliferation Cells Cessation of life DNA Damage Databases Development Enzymes Epidermal Growth Factor Receptor ErbB Receptor Family Protein Exhibits Fibroblasts Fluorescent in Situ Hybridization Foundations Functional disorder Future Galactosidase Genes Growth Human IGFBP3 gene IGFBP5 gene Immunohistochemistry Insulin-Like-Growth Factor I Receptor Integral Membrane Protein Lesion Malignant Neoplasms Malignant neoplasm of ovary Mediating Mediator of activation protein Molecular Molecular Analysis Monoclonal Antibodies Morphology Names Oncogene Activation Oncogenic Pathway interactions Patients Phenotype Phosphorylation Platelet-Derived Growth Factor Receptor Premalignant Process Proliferating Protein Tyrosine Kinase Proteins Receptor Inhibition Receptor Protein-Tyrosine Kinases Receptor Signaling Recombinants Recurrence Research Resistance Resistance development Roche brand of trastuzumab Signal Pathway Therapeutic Trastuzumab Treatment Efficacy Tumor Cell Line Tumor-Derived United States Up-Regulation Uterine Cancer Woman Xenograft procedure base cell growth clinical efficacy combat inhibitor/antagonist malignant breast neoplasm malignant stomach neoplasm member outcome forecast overexpression premature public health relevance receptor expression research study response senescence standard of care telomere therapeutic target tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Herceptin/trastuzumab is a monoclonal antibody that selectively targets the Her2 protein and remains the standard of care for Her2-positive breast cancer. Nevertheless, the biological processes altered by trastuzumab to impede cancer progression are presently unclear. Results from our preliminary studies show that trastuzumab causes cellular senescence in both cultured breast cancer cells and tumors derived from human patients who have undergone treatment in adjuvant therapy. This observed senescent phenotype is associated with several hallmarks of senescence including an inability to proliferate, induction of the cell cycle inhibitors p16 and p21, senescence-associated ?-galactosidase activity, and upregulation of the secreted proteins IGFBP3 and IGFBP5. Previous studies have indicated that high-level expression of the insulin-like growth factor 1 receptor (IGF1R) is associated with a lower response rate to trastuzumab. Consistent with this, elevated levels of IGF1R expression and phosphorylation were found in trastuzumab-resistant breast cancer cells following Her2 inhibition. Importantly, trastuzumab resistance can be overcome by combining trastuzumab with either a selective IGF1R inhibitor or recombinant IGFBPs, resulting in cellular senescence. Collectively, these results reveal the biological underpinnings of trastuzumab's clinical efficacy and suggest a practical approach for the treatment of Her2-positive, trastuzumab-resistant breast cancer. Capitalizing on these new findings, we propose the following two specific aims to explore the molecular basis that distinguish breast cancer patients who are sensitive to trastuzumab from those who are resistant. Aim 1 will assess the potential contributions of several mechanisms that may control the expression level of IGF1R associated with sensitivity/resistance to trastuzumab. Aim 2 will explore whether tyrosine kinase receptors, in addition to IGF1R, could be involved in the development of a trastuzumab-resistant phenotype. Together results from these exploratory experiments will lay the foundation a systemic analysis of molecular determinants at the mechanistic level for sensitivity and resistant to this standard therapy for Her2-positive breast cancer can be conducted in the future.

描述（由申请人提供）：赫赛汀/曲妥珠单抗是一种单克隆抗体，选择性靶向 Her2 蛋白，并且仍然是 Her2 阳性乳腺癌的标准治疗方法。然而，曲妥珠单抗改变生物过程以阻止癌症进展目前尚不清楚。我们的初步研究结果表明，曲妥珠单抗会导致培养的乳腺癌细胞和来自接受辅助治疗的人类患者的肿瘤细胞衰老。这种观察到的衰老表型与衰老的几个标志相关，包括无法增殖、细胞周期抑制剂 p16 和 p21 的诱导、衰老相关的 β-半乳糖苷酶活性以及分泌蛋白 IGFBP3 和 IGFBP5 的上调。先前的研究表明，胰岛素样生长因子 1 受体 (IGF1R) 的高水平表达与曲妥珠单抗的较低反应率相关。与此一致的是，在 Her2 抑制后，在曲妥珠单抗耐药乳腺癌细胞中发现 IGF1R 表达和磷酸化水平升高。重要的是，通过将曲妥珠单抗与选择性 IGF1R 抑制剂或重组 IGFBP 联合使用，可以克服曲妥珠单抗耐药性，从而导致细胞衰老。总的来说，这些结果揭示了曲妥珠单抗临床疗效的生物学基础，并提出了治疗 Her2 阳性、曲妥珠单抗耐药乳腺癌的实用方法。利用这些新发现，我们提出以下两个具体目标，以探索区分对曲妥珠单抗敏感和耐药的乳腺癌患者的分子基础。目标 1 将评估可能控制与曲妥珠单抗敏感性/耐药相关的 IGF1R 表达水平的几种机制的潜在贡献。目标 2 将探讨除 IGF1R 之外，酪氨酸激酶受体是否可能参与曲妥珠单抗耐药表型的发展。这些探索性实验的结果将为将来在机制水平上对 Her2 阳性乳腺癌标准疗法的敏感性和耐药性分子决定因素进行系统分析奠定基础。