Targeted Intervention of Breast Oncogenic Pathways

项目描述（由申请人提供）：该项目的总体目标是了解Mek/Erk、JAK/STAT3和PI3K/Akt在乳腺癌发生中的作用，并制定更有效的乳腺癌治疗新策略。受体酪氨酸激酶ErbB2在人类乳腺癌中过度表达，这与预后不良有关。ErbB2与ErbB1（EGFR）、ErbB3或ErbB4异源二聚并刺激多种信号转导通路，导致乳腺癌中组成性激活Akt、STAT3和Erkl/2。它仍然是;然而，目前尚不清楚这些途径中哪一条对于维持恶性转化最为重要。此外，Mek/Erk、JAK/STAT3和PI3K/Akt通路在乳腺癌发生和治疗结果中的作用尚不清楚。我们和其他人已经开发了这些信号通路的干扰物，包括ErbB2抗体和ErbB1酪氨酸激酶、Mek和PI3K激酶、JAK/STAT3信号和法尼基转移酶的抑制剂，法尼基转移酶是激活法尼基化蛋白（如激活Mek/Erk和PI3K/Akt通路的Ras）所需的酶。在本项目中，我们提出验证组成性激活Mek/Erk、JAK/STAT3和/或PI3K/Akt通路参与乳腺癌发生和肿瘤耐药的假设，以及靶向干预这些通路阻断恶性转化、诱导细胞凋亡和使乳腺肿瘤对化疗敏感的假设。这一假设将通过以下具体目的进行验证：1)研究组成性激活的PI3K/Akt、JAK/STAT3和Mek/Erk在乳腺癌发生中的作用。在这里，我们将确定这些途径的遗传和药理破坏是否逆转恶性转化并诱导细胞凋亡。将使用PI3K、Akt、Mek、STAT3和Ras的显性阴性形式。JAK/STAT3通路、PI3K、Mek和法尼基转移酶的药物抑制剂也将单独或联合使用。2)确定ErbB2和/或EGFR过表达的乳腺癌细胞对赫赛汀或易瑞沙的耐药是否由于组成性激活Akt/PI3K、JAK/STAT3和/或MEK/Erk通路。为此，我们将确定这些通路的抑制剂是否会使乳腺癌细胞对赫赛汀和/或易瑞沙敏感。3)通过靶向药物干预PI3K/Akt、Mek/Erk和/或JAK/STAT3通路，是否可以克服乳腺癌细胞对阿霉素、环磷酰胺和/或泰索帝的耐药。4)在局部晚期乳腺癌和转移性乳腺癌患者中开展假设驱动的术前阿霉素(a)、环磷酰胺(C)和FTI R115777 （Zarnestra）的I/lI期临床试验。在这里，我们将确定治疗前的ErbB1、ErbB2、ErbB3和/或ErbB4水平，以及Akt、STAT3和/或Erkl/2磷酸化水平是否能预测AC/FTI的临床反应。我们还将把临床反应与抑制蛋白法尼化的能力和磷酸化Akt、磷酸化Erkl/2和/或磷酸化STAT3的水平联系起来。这些研究的结果将增强我们对Mek/Erk、JAK/STAT3和PI3K/Akt通路在乳腺癌发生和治疗结果中的作用的理解，并将改进人类乳腺癌的治疗方法。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the role of the oncogenic and tumor survival pathways, Mek/Erk, JAK/STAT3 and PI3K/Akt in breast oncogenesis and to develop new strategies for more effective breast cancer treatment. The receptor tyrosine kinase ErbB2 is overexpressed in human breast cancer and this is associated with poor prognosis. ErbB2 heterodimerizes with ErbB1(EGFR), ErbB3 or ErbB4 and stimulates many signal transduction pathways leading to the constitutively activated Akt, STAT3 and Erkl/2 in breast cancer. It remains; however, unclear which of these pathways are most important for maintaining malignant transformation. Furthermore, the contribution of Mek/Erk, JAK/STAT3 and PI3K/Akt pathways to breast oncogenesis and treatment outcome is not known. We and others have developed disrupters of these signaling pathways including antibodies to ErbB2 and inhibitors of ErbB1 tyrosine kinase, Mek and PI3K kinases, JAK/STAT3 signaling and farnesyltransferase, an enzyme required for the activation of farnesylated proteins such as Ras which activates Mek/Erk and PI3K/Akt pathways. In this project we propose to test the hypothesis that constitutively activated Mek/Erk, JAK/STAT3 and/or PI3K/Akt pathways contribute to breast oncogenesis and tumor resistance, and that targeted intervention of these pathways blocks malignant transformation, induces apoptosis and sensitizes breast tumors to chemotherapy. This hypothesis will be tested through the following specific aims: 1) To investigate the role of constitutively activated PI3K/Akt, JAK/STAT3 and Mek/Erk, in breast cancer oncogenesis. Here we will determine if genetic and pharmacological disruptions of these pathways reverse malignant transformation and induce apoptosis. Dominant negative forms of PI3K, Akt, Mek, STAT3 and Ras will be used. Pharmacological inhibitors of JAK/STAT3 pathway, PI3K, Mek and farnesyltransferase will also be used individually or in combination. 2) To determine if resistance to Herceptin or Iressa of ErbB2 and/or EGFR overexpressing breast cancer cells is due to constitutively activated Akt/PI3K, JAK/STAT3 and/or MEK/Erk pathways. To this end, we will determine if inhibitors of these pathways sensitize breast cancer cells to Herceptin and/or Iressa. 3) To determine if resistance of breast cancer cells to Adriamycin, cyclophosphamide and/or taxotere could be overcome by targeted pharmacological intervention of PI3K/Akt, Mek/Erk and/or JAK/STAT3 pathways. 4) To conduct a hypothesis-driven phase I/lI clinical trial of preoperative Adriamycin (A), cyclophosphamide (C) and FTI R115777 (Zarnestra) in patients with locally advanced breast cancer and metastatic breast cancer. Here we will determine if pre-treatment levels of ErbB1, ErbB2, ErbB3 and/or ErbB4, and phosphorylated levels of Akt, STAT3 and/or Erkl/2 predict clinical response to AC/FTI. We will also correlate clinical response to ability to suppress protein farnesylation and the levels of phospho Akt, phospho Erkl/2 and/or phospho STAT3. Results from these studies will enhance our understanding of the role of Mek/Erk, JAK/STAT3 and PI3K/Akt pathways in breast cancer oncogenesis and treatment outcome and will result in improved therapies of human breast cancers.