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

HER-2/IGF-IR 串扰和赫赛汀耐药

• 批准号: 7922250
• 负责人: RITA NAHTA
• 金额: $ 10.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922250
• 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独立研究员，专注于乳腺癌耐药性的分子机制，对靶向治疗和生长因子受体特别感兴趣。该 K01 奖将帮助她转型为完全独立的科学研究者。接下来的一两年对于提高她的分子生物学技能以及在博士的指导下开发纳米技术和动物模型领域的新技能至关重要。弗朗西斯科·J·埃斯特瓦 (Francisco J. Esteva) 和洪敏杰 (Mien-Chie Hung)。 M.D.安德森癌症中心为实施拟议的研究计划提供了良好的协作环境。博士。 Esteva 和 Hung 在科学界享有盛誉，Nahta 博士将受益于他们在信号转导、耐药性、分子治疗、细胞周期调控和转化研究领域的综合专业知识。 Esteva 博士领导的乳腺癌转化研究实验室是 Hung 博士领导的乳腺癌研究计划的一个组成部分。该项目充满启发性的智力和科学环境将极大地促进 Nahta 博士的职业发展。 Nahta 博士目前的研究重点是 HER-2 靶向抗体 Herceptin 耐药的分子机制。使用她开发的赫赛汀耐药体外模型，她观察到以下情况：1) HER-2 在耐药细胞中与 IGF-IR 形成独特的异二聚体。该复合物中的 HER-2 被磷酸化，表明 IGF-IR 与 HER-2 存在串扰； 2) 位于 HER-2 和 IGF-IR 下游的 p27kip1 在耐药细胞中下调。 p27kip1 的异位表达可恢复赫赛汀敏感性。基于这些发现，本申请的中心假设是赫赛汀耐药性是通过乳腺癌细胞中 HER-2 与 IGFIR 的结合增加以及随后 p27kip1 的降解介导的。我们的具体目标是： 1) 表征 HER-2 和 IGF-IR 之间的相互作用； 2) 明确HER-2/IGF-IR下调p27kip1的分子机制； 3) 研究 HER-2/IGF-IR 作为体内治疗靶点。我们将使用 GST Pulldown 测定、纳米技术、蛋白质测定、PCR、siRNA 转染和小鼠体内研究。我们的研究最终将能够识别最有可能对赫赛汀产生反应的肿瘤，并将指导针对 HER-2 过表达乳腺癌开发更有效的靶向疗法。