Molecular determinants underlying herceptin sensitivity and resistance

赫赛汀敏感性和耐药性的分子决定因素

• 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
• 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

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（由申请方提供）：赫赛汀/曲妥珠单抗是一种选择性靶向Her 2蛋白的单克隆抗体，仍是Her 2阳性乳腺癌的标准治疗。然而，目前尚不清楚曲妥珠单抗改变生物学过程以阻止癌症进展。我们的初步研究结果表明，曲妥珠单抗在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中均引起细胞衰老。这种观察到的衰老表型与衰老的几个标志有关，包括不能增殖，诱导细胞周期抑制剂p16和p21，衰老相关的？半乳糖苷酶活性，以及分泌蛋白IGFBP 3和IGFBP 5的上调。先前的研究表明，胰岛素样生长因子1受体（IGF 1 R）的高水平表达与曲妥珠单抗的较低反应率相关。与此一致，在Her 2抑制后，在曲妥珠单抗耐药乳腺癌细胞中发现IGF 1 R表达和磷酸化水平升高。重要的是，曲妥珠单抗耐药性可以通过曲妥珠单抗与选择性IGF 1 R抑制剂或重组IGFBPs组合来克服，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Her 2阳性、曲妥珠单抗耐药乳腺癌的实用方法。利用这些新发现，我们提出了以下两个具体目标，以探索区分对曲妥珠单抗敏感的乳腺癌患者与耐药患者的分子基础。目的1将评估可能控制与曲妥珠单抗敏感性/耐药相关的IGF 1 R表达水平的几种机制的潜在贡献。目的2将探讨酪氨酸激酶受体，除了IGF 1 R，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对Her 2阳性乳腺癌标准疗法的敏感性和耐药性在机制水平上进行分子决定因素的系统分析奠定基础。