The PI3K/PTEN/AKT Signal Transduction Cascade in Breast Cancer

描述(由申请人提供)：在过去的10年中，乳腺癌的预后有了显著的改善。然而，大量患者仍然复发，而另一些患者则接受了不必要的治疗，因为我们无法区分患者患有的是低风险疾病还是高风险疾病。乳腺癌的行为在一定程度上受到PI3K/PTEN/AKT信号通路的调控，该通路与激素受体双向相互作用，并在多个水平上进一步相互作用，形成一个复杂的信号网络。我的假设是，乳腺癌可以通过PI3K/PTEN/AKT通路中蛋白质信号的变化来分类，并且可以通过识别和靶向这一通路来预测和改善肿瘤对特定治疗方案的反应。我的具体目标是：(1)通过表征PI3K/PTEN/AKT信号转导通路的功能蛋白质组表达/激活信号转导通路的功能蛋白质组特征，对乳腺癌进行分类；(2)确定拟议的基于蛋白质组学的分类是否反映了术前紫杉醇(紫杉醇或多西紫杉醇)、多柔比星/表红霉素和环磷酰胺(紫杉醇-FA/EC)化疗的疗效；以及(3)确定针对PI3K/PTEN/AKT通路的治疗干预结合化疗对三种受体(ER、PR和HER2)阴性的局部晚期乳腺癌(LABC)是否有效。我们将对90例冷冻乳腺癌标本进行逆相蛋白芯片分析(RPPA)，并分析PI3K/PTEN/AKT级联。这些数据将被用作训练集，以定义与术前化疗反应相关的乳腺癌信号特征。我们将获得50个样本的验证集，并应用蛋白质组学分析来确定其在预测治疗反应方面的特异性和敏感性。我们将开发一项针对三受体阴性LABC女性的II期随机临床试验，患者将接受标准化疗(多西紫杉醇和FEC)或多西紫杉醇加RAD001和FEC治疗。这项研究将揭示在三受体阴性乳腺癌患者的标准新辅助化疗中加入mTOR抑制剂是否会导致PI3K/PTEN/AKT通路的分子变化(抑制/激活)以及这种干预的临床效果。这项研究将有助于更好地理解乳腺癌行为和治疗反应性存在巨大差异的潜在机制，并将确定常规治疗不适用的患者的其他治疗靶点。同时，它将为我提供必要的经验、知识和技能，以启动和开展乳腺肿瘤学的独立翻译研究事业。预计这个项目的结果将使我能够在拟议奖项的第四年提交一份竞争性的R01申请。

DESCRIPTION (provided by applicant): Breast cancer outcome has improved significantly over the last 10 years. However, an important number of patients still relapse, while others receive unnecessary therapy as we are unable to distinguish whether patients have low-risk or high-risk disease. Breast cancer behavior is regulated, in part, by the PI3K/PTEN/AKT signaling pathway, which interact bidirectionally with hormone receptors and further interacts at multiple levels, creating a complex signaling network. My hypothesis is that breast cancer tumors can be classified by changes in protein signaling in the PI3K/PTEN/AKT pathway and that tumor response to specific therapeutic regimens can be predicted and improved by identifying and targeting this pathway. My specific aims are: (1) To classify breast cancers by characterizing the functional proteomic expression/activation signature of the PI3K/PTEN/AKT signal transduction cascade, (2) To determine whether the proposed functional proteomics-based classification reflects response to preoperative taxane (paclitaxel or docetaxel) and 5-fluoruracil, doxorubicin/epirrubicin, and cyclophosphamide (paclitaxel-FA/EC) chemotherapy, and (3) To determine whether a therapeutic intervention targeting the PI3K/PTEN/AKT pathway in combination with chemotherapy is an effective treatment for triple receptor (ER, PR, and HER2)- negative locally advanced breast cancer (LABC). We will perform reverse-phase protein microarray analysis (RPPA) of 90 frozen preoperative breast cancer samples and analyze the PI3K/PTEN/AKT cascade. The data will be used as a training set to define a breast cancer signaling profile associated with response to preoperative chemotherapy. We will obtain a validation set of 50 samples and apply the proteomic profile to determine its specificity and sensitivity in predicting response to therapy. We will develop a phase II randomized clinical trial in women with triple receptor-negative LABC in which patients will be treated with either standard chemotherapy (docetaxel followed by FEC) or docetaxel plus RAD001 followed by FEC. This study will reveal whether the addition of an mTOR inhibitor to standard neoadjuvant chemotherapy in patients with triple receptor-negative breast cancer causes molecular changes (inhibition/activation) in the PI3K/PTEN/AKT pathway and the clinical effects of this intervention. This study will lead to a better understanding of the mechanisms underlying the wide variation in breast cancer behavior and therapy responsiveness and will also identify other therapeutic targets in patients for whom conventional therapy is inadequate. At the same time it will provide me with the experience, knowledge, and skills necessary to launch and conduct an independent translational research career in breast oncology. The outcome of this project is expected to position me to submit a competitive R01 application during the fourth year of the proposed award.