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

描述（由申请人提供）：此修订提案描述了一个为期5年的指导研究项目，旨在将申请人转变为独立的转化科学家。在项目期间，首席研究员（p.l.）将努力拓宽他的知识基础和必要的技术技能，最终指导一个成功的基于实验室的癌症生物学项目。P.l.的发展将由癌症生物学领域的知名专家尼尔·罗森博士（Dr. Neal Rosen）持续指导，他在一个以培养癌症研究的临床科学家而闻名的机构工作。纪念斯隆-凯特琳癌症中心。申请人的研究重点是活化的PI3K-AKT信号在乳腺癌中的功能研究。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受体二聚化激活PI3K-AKT通路。申请人现在报告PI3K-AKT通路的激活产生针对ErbB3受体的抑制信号。该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。该提案将测试三个假设：(1)PI3K-AKT通路调节一组控制ErbB3受体表达的离散信号。(2)通过PI3K-AKT通路调控ErbB3的表达可以阻止肿瘤发生，但最终在侵袭性癌症中被克服。(3)结合抑制ErbB3诱导的治疗策略将比单独抑制HER2或AKT更有效。在目的1中，我们将使用药理学和遗传学方法来确定PI3K-AKT调控ErbB3表达的背景和机制。在Aim 2中，我们将确定ErbB3表达失调对肿瘤形成的影响，并评估这种情况是否发生在人类肿瘤样本中。在Aim 3中，我们将在HER2扩增的乳腺癌模型中评估联合抑制AKT和HER1/2或选择性抑制ErbB3的疗效。这些研究的总体目标是详细说明活化的PI3K-AKT信号在乳腺癌中的全部后果，并开发针对失调的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.