HER-2/IGF-IR cross-talk and Herceptin resistance

HER-2/IGF-IR 串扰和赫赛汀耐药

• 批准号: 7650200
• 负责人: RITA NAHTA
• 金额: $ 14.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650200
• 关键词: Animal Model; Antibodies; Area; Binding; Biological Assay; Breast Cancer Cell; Cancer Center; Cancer Research Project; Cell Cycle Regulation; Cells; Communities; Complex; Data; Development; Down-Regulation; Drug resistance; ERBB2 gene; Ectopic Expression; Environment; Experimental Models; Glutathione S-Transferase; Goals; Growth; Growth Factor Receptors; Image; Immunoblotting; Immunoprecipitation; In Vitro; Laboratories; Life; Mass Spectrum Analysis; Mediating; Mentored Research Scientist Development Award; Mentorship; Modeling; Molecular; Molecular Biology; Mus; Nanotechnology; Patients; Peptides; Pharmaceutical Preparations; Polishes; Proteins; Qualifying; Research; Research Personnel; Resistance; Resistance development; Roche brand of trastuzumab; Signal Transduction; Small Interfering RNA; Survival Rate; Therapeutic; Translational Research; base; career; career development; cyclin-dependent kinase inhibitor 1B; effective therapy; in vitro Model; in vivo; in vivo Model; innovation; interest; malignant breast neoplasm; mutant; novel; overexpression; prevent; programs; protein degradation; resistance mechanism; skills; therapeutic target; tumor; ubiquitin ligase

DESCRIPTION (provided by applicant): Dr. Rita Nahta's career goal is to become an independent researcher focused on the molecular mechanisms of drug resistance in breast cancer with a specific interest in targeted therapeutics and growth factor receptors. This K01 Award will assist her transition to a fully independent scientific investigator. The next year or two will be critical for polishing her molecular biology skills and developing new skills in the areas of nanotechnology and animal models under the mentorship of Drs. Francisco J. Esteva and Mien-Chie Hung. The M. D. Anderson Cancer Center offers an excellent collaborative environment for implementation of the proposed research plan. Drs. Esteva and Hung are highly regarded among the scientific community, and Dr. Nahta will benefit from their combined expertise in the areas of signal transduction, drug resistance, molecular therapeutics, cell cycle regulation and translational research. The Breast Cancer Translational Research Laboratory, which is directed by Dr. Esteva, is an integral component of the Breast Cancer Research Program directed by Dr. Hung. The stimulating intellectual and scientific environment of this program will greatly enhance Dr. Nahta's career development. Dr. Nahta's current research focus is on the molecular mechanisms of resistance to the HER-2-targeted antibody Herceptin. Using an in vitro model of Herceptin resistance that she developed, she observed the following: 1) HER-2 forms a unique heterodimer with IGF-IR in resistant cells. HER-2 in this complex is phosphorylated, suggesting cross-talk from IGF-IR to HER-2; 2) p27kip1, which lies downstream of both HER-2 and IGF-IR, is downregulated in resistant cells. Ectopic expression of p27kip1 restores Herceptin sensitivity. Based on these findings, the central hypothesis of this application is that Herceptin resistance is mediated by increased binding of HER-2 to IGFIR with subsequent degradation of p27kip1 in breast cancer cells. Our specific aims are to: 1) Characterize the interaction between HER-2 and IGF-IR; 2) Define the molecular mechanism by which HER-2/IGF-IR downregulates p27kip1; 3) Investigate HER-2/IGF-IR as a therapeutic target in vivo. We will use GST pulldown assays, nanotechnology, protein assays, PCR, siRNAtransfection, and in vivo mouse studies. Our studies will ultimately allow the identification of tumors most likely to respond to Herceptin, and will guide the development of more effective targeted therapies for HER-2-overexpressing breast cancer.

描述（由申请人提供）：Rita Nahta博士的职业目标是成为一名专注于乳腺癌耐药性分子机制的独立研究人员，对靶向治疗和生长因子受体具有特定的兴趣。该K01奖将有助于她向完全独立的科学研究者过渡。在DRS的指导下，接下来的一两年对于练习她的分子生物学技能和在纳米技术和动物模型领域发展新技能至关重要。 Francisco J. Esteva和Mien-Chie Hung。 M. D. Anderson癌症中心为实施拟议的研究计划提供了极好的协作环境。博士。 Esteva和Hung在科学界受到了高度评​​价，Nahta博士将受益于其在信号转导，耐药性，分子疗法，细胞周期调节和转化研究领域的综合专业知识中受益。由Esteva博士执导的乳腺癌转化研究实验室是Hung博士指导的乳腺癌研究计划的组成部分。该计划的刺激性智力和科学环境将极大地增强Nahta博士的职业发展。 Nahta博士当前的研究重点是对靶向HER-2靶向抗体的抗体的分子机制。她使用了她开发的赫赛普抗蛋白耐药性的体外模型，观察到以下几点：1）HER-2在抗性细胞中与IGF-IR形成独特的异二聚体。在这种复合物中的HER-2被磷酸化，表明从IGF-IR到HER-2的串扰。 2）P27KIP1位于HER-2和IGF-IR的下游，在抗性细胞中被下调。 p27KIP1的异位表达恢复了赫赛汀的敏感性。基于这些发现，该应用的核心假设是，赫赛汀的耐药性是通过增加HER-2与IgFir的结合，随后在乳腺癌细胞中P27KIP1降解的结合。我们的具体目的是：1）表征HER-2和IGF-IR之间的相互作用； 2）定义HER-2/IGF-IR下调P27KIP1的分子机制； 3）在体内研究HER-2/IGF-IR作为治疗靶点。我们将使用GST下拉分析，纳米技术，蛋白质测定，PCR，sirnatransfection和体内小鼠研究。我们的研究最终将允许鉴定最有可能对赫赛汀反应的肿瘤，并将指导开发更有效的针对HER-2过表达乳腺癌的靶向疗法。