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

Rita Nahta博士的职业目标是成为一名独立的研究人员，专注于乳腺癌耐药的分子机制，对靶向治疗和生长因子受体有特殊的兴趣。这个K01奖将帮助她过渡到一个完全独立的科学研究者。接下来的一两年将是她在纳米技术和动物模型领域的指导下，提高分子生物学技能和发展新技能的关键。弗朗西斯科·j·埃斯特瓦和洪明智。m.d.安德森癌症中心为实施拟议的研究计划提供了一个良好的合作环境。Drs。Esteva和Hung在科学界享有很高的声誉，Nahta博士将从他们在信号转导、耐药、分子治疗、细胞周期调节和转化研究领域的综合专业知识中受益。乳腺癌转化研究实验室由Esteva博士领导，是Hung博士领导的乳腺癌研究项目的一个组成部分。这个项目充满激情的学术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。利用她开发的赫赛汀耐药体外模型，她观察到以下现象：1)HER-2在耐药细胞中与IGF-IR形成独特的异源二聚体。这个复合体中的HER-2被磷酸化，表明IGF-IR与HER-2相互作用；2) p27kip1位于HER-2和IGF-IR的下游，在耐药细胞中下调。p27kip1异位表达可恢复赫赛汀敏感性。基于这些发现，本应用的中心假设是Herceptin耐药是由HER-2与IGFIR结合增加以及随后乳腺癌细胞中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)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、蛋白质分析、PCR、sirnat转染和小鼠体内研究。我们的研究最终将允许识别最有可能对赫赛汀有反应的肿瘤，并将指导开发更有效的靶向治疗her -2过表达乳腺癌的方法。

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.