Targeted Intervention of Breast Oncogenic Pathways

描述(申请人提供)：这个项目的总体目标是了解致癌和肿瘤生存途径，MEK/ERK，JAK/STAT3和PI3K/Akt在乳腺癌发生中的作用，并开发更有效的乳腺癌治疗的新策略。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，刺激多种信号转导通路，导致乳腺癌中Akt、STAT3和Erk1/2的结构性激活。然而，目前还不清楚这些途径中哪些对维持恶性转化最重要。此外，MEK/Erk、JAK/STAT3和PI3K/Akt通路在乳腺肿瘤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出这些信号通路的干扰物，包括ErbB2的抗体和ErbB1酪氨酸激酶、MEK和PI3K激酶的抑制剂，JAK/STAT3信号和法尼基转移酶，法尼基转移酶是激活法尼化蛋白所必需的酶，如RAS，它激活MEK/Erk和PI3K/Akt通路。在这个项目中，我们建议验证这样一种假设，即结构性激活的MEK/Erk、JAK/STAT3和/或PI3K/Akt通路有助于乳腺肿瘤的发生和肿瘤耐药，并且这些通路的靶向干预阻止了恶性转化，诱导了细胞凋亡，并使乳腺肿瘤对化疗敏感。这一假说将通过以下特定目的来验证：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物干扰是否会逆转恶性转化并诱导细胞凋亡。将使用PI3K、Akt、MEK、STAT3和RAS的主要否定形式。JAK/STAT3途径的药理抑制剂、PI3K、MEK和法尼基转移酶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Herceptin或Iressa的耐药性是否与Akt/PI3K、JAK/STAT3和/或MEK/Erk通路的结构性激活有关。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)研究靶向药物干预PI3K/Akt、MEK/Erk和/或JAK/STAT3通路能否克服乳腺癌细胞对阿霉素、环磷酰胺和/或紫杉醇的耐药性。4)对局部晚期乳腺癌和转移性乳腺癌患者术前应用阿霉素(A)、环磷酰胺(C)和FTI R115777(Zarnestra)进行假说驱动的I/LI期临床试验。在这里，我们将确定治疗前ErbB1、ErbB2、ErbB3和/或ErbB4的水平以及Akt、STAT3和/或Erk1/2的磷酸化水平是否可以预测AC/FTI的临床疗效。我们还会将抑制蛋白法尼化能力的临床反应与磷酸化Akt、磷酸化Erk1/2和/或磷酸化STAT3的水平联系起来。这些研究的结果将加深我们对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，并将有助于改进人类乳腺癌的治疗。

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.