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

描述（由申请人提供）：在过去的10年里，乳腺癌的预后有了显著的改善。然而，仍然有相当数量的患者复发，而其他患者接受不必要的治疗，因为我们无法区分患者是低风险还是高风险的疾病。乳腺癌行为在一定程度上受PI3K/PTEN/AKT信号通路的调控，该信号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。我的假设是乳腺癌肿瘤可以通过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该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信号转导级联的功能蛋白质组学表达/激活特征来对乳腺癌进行分类；(2)确定基于功能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）和5-氟尿嘧啶、阿霉素/表柔比星、环磷酰胺（紫杉醇- fa /EC）化疗的反应。(3)确定针对PI3K/PTEN/AKT通路的治疗干预联合化疗是否能有效治疗三受体（ER、PR和HER2）阴性的局部晚期乳腺癌（LABC）。我们将对90例冷冻乳腺癌术前样本进行逆相蛋白微阵列分析（RPPA），并分析PI3K/PTEN/AKT级联。这些数据将被用作训练集，以确定与术前化疗反应相关的乳腺癌信号谱。我们将获得50个样本的验证集，并应用蛋白质组学谱来确定其预测治疗反应的特异性和敏感性。我们将在三受体阴性LABC女性患者中开展一项II期随机临床试验，患者将接受标准化疗（多西紫杉醇加FEC）或多西紫杉醇加RAD001加FEC。本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抑制剂是否会引起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了解乳腺癌行为和治疗反应性广泛变化的机制，并将确定传统治疗不充分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，以启动和开展独立的乳腺肿瘤学转化研究事业。这个项目的结果预计将使我在拟议奖项的第四年提交一份有竞争力的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.