Biologic and therapeutic implications of Akt activation in Her2+ breast cancer

描述(由申请人提供)：本修订方案描述了一项为期5年的指导性研究项目，旨在将申请人转变为一名独立的翻译科学家。在项目期间，首席调查员(P.L.)将致力于扩大他的知识基础和必要的技术技能，以最终监督一个成功的癌症生物学实验室项目。中国人民解放军的发展历程。将由癌症生物学领域的知名专家尼尔·罗森博士持续指导，该机构以培训癌症研究方面的临床科学家而闻名。纪念斯隆-凯特琳癌症中心。申请人的研究重点是研究激活的PI3K-AKT信号在乳腺癌中的功能。这一途径在许多乳腺癌中被激活，包括那些以HER2扩增为特征的乳腺癌。HER2/ErbB2主要通过与HER3/ErbB3受体二聚体激活PI3K-AKT通路。申请人现在报告说，PI3K-AKT通路的激活产生了针对ErbB3受体的抑制信号。这项建议旨在阐明这些抑制信号在肿瘤形成和维持中的机制和后果。该提案将检验三个假设：(1)PI3K-AKT途径调节一组控制ErbB3受体表达的离散信号。(2)通过PI3K-AKT途径调节ErbB3的表达可以抑制肿瘤的发生，但在浸润性癌症中最终会被克服。(3)联合抑制ErbB3诱导的治疗策略将比单独抑制HER2或AKT更有效。在目标1中，我们将使用药理学和遗传操作来确定PI3K-AKT调节ErbB3表达的背景和机制。在目标2中，我们将确定解除调控的ErbB3表达对肿瘤形成的影响，并评估这种情况是否发生在人类肿瘤样本中。在目的3中，我们将评估AKT和HER1/2联合抑制或选择性抑制ErbB3在HER2扩增乳腺癌模型中的疗效。这些研究的总体目标是详细说明激活的PI3K-AKT信号在乳腺癌中的全部后果，并开发针对调控失调的AKT作为治疗方法的新策略。

DESCRIPTION (provided by applicant): This revised proposal describes a 5 year mentored research project designed to transition the applicant into an independent translational scientist. During the project period, the Principal Investigator (P.l.) will devote efforts towards broadening his knowledge base and technical skills as necessary to ultimately supervise a successful laboratory based program in cancer biology. The development of the P.l. will be fostered by ongoing mentorship by an established expert in the field of cancer biology, Dr. Neal Rosen, at an institution renowned for training clinician scientists in cancer research. Memorial Sloan-Kettering Cancer Center. The focus of the applicant's research is the study of the functions of activated PI3K-AKT signaling in breast cancer. This pathway is activated in many breast cancers including those characterized by HER2 amplification. HER2/ErbB2 primarily activates the PI3K-AKT pathway by dimerizing with the HER3/ErbB3 receptor. The applicant now reports that activation of the PI3K-AKT pathway generates inhibitory signals against the ErbB3 receptor. This proposal is aimed at elucidating the mechanisms and consequences of these inhibitory signals in tumor formation and maintenance. The proposal will test three hypotheses: (1) The PI3K-AKT pathway regulates a discrete set of signals that control the expression of the ErbB3 receptor. (2) The regulation of ErbB3 expression by the PI3K-AKT pathway can impede tumorigenesis but is ultimately overcome in invasive cancers. (3) Therapeutic strategies that incorporate inhibition of ErbB3 induction will be more effective than inhibition of HER2 or AKT alone. In Aim 1, we will use pharmacologic and genetic manipulations to determine both the context and mechanism of PI3K-AKT regulation of ErbB3 expression. In Aim 2, we will determine the effect of deregulated ErbB3 expression upon tumor formation and evaluate whether this takes place in human tumor samples. In Aim 3, we will evaluate the efficacy of combined inhibition of AKT and HER1/2 or selective inhibition of ErbB3 in models of HER2 amplified breast cancer. The overall goal of these studies is to detail the full consequences of activated PI3K-AKT signaling in breast cancer and to develop novel strategies that target dysregulated AKT as therapeutic approaches.