Targeted Intervention of Breast Oncogenic Pathways

描述（由申请人提供）：本项目的总体目标是了解致癌和肿瘤生存途径Mek/Erk、JAK/STAT 3和PI 3 K/Akt在乳腺癌发生中的作用，并开发更有效的乳腺癌治疗新策略。受体酪氨酸激酶ErbB 2在人乳腺癌中过表达，这与不良预后相关。ErbB 2与ErbB 1（EGFR）、ErbB 3或ErbB 4异源二聚化，并刺激许多信号转导通路，导致乳腺癌中Akt、STAT 3和Erk 1/2的组成性激活。它仍然是;然而，不清楚这些途径是最重要的维持恶性转化。此外，Mek/Erk、JAK/STAT 3和PI 3 K/Akt通路对乳腺癌发生和治疗结果的贡献尚不清楚。我们和其他人已经开发了这些信号传导途径的破坏剂，包括ErbB 2的抗体和ErbB 1酪氨酸激酶、Mek和PI 3 K激酶、JAK/STAT 3信号传导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Ras所需的酶，其激活Mek/Erk和PI 3 K/Akt途径。在本项目中，我们建议测试以下假设：组成性激活的Mek/Erk、JAK/STAT 3和/或PI 3 K/Akt途径有助于乳腺癌的发生和肿瘤耐药性，并且这些途径的靶向干预可以阻止恶性转化、诱导细胞凋亡并使乳腺癌对化疗敏感。1）研究组成性激活的PI 3 K/Akt、JAK/STAT 3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学干扰逆转恶性转化和诱导细胞凋亡。将使用PI 3 K、Akt、Mek、STAT 3和Ras的显性阴性形式。JAK/STAT 3途径、PI 3 K、Mek和法尼基转移酶的药理学抑制剂也将单独或组合使用。2)确定ErbB 2和/或EGFR过表达乳腺癌细胞对赫赛汀或易瑞沙的耐药性是否是由于组成性激活的Akt/PI 3 K、JAK/STAT 3和/或MEK/Erk通路。为此，我们将确定这些途径的抑制剂是否使乳腺癌细胞对赫赛汀和/或易瑞沙敏感。3)确定是否可以通过PI 3 K/Akt、Mek/Erk和/或JAK/STAT 3通路的靶向药物干预来克服乳腺癌细胞对阿霉素、环磷酰胺和/或泰索帝的耐药性。4)在局部晚期乳腺癌和转移性乳腺癌患者中进行术前阿霉素（A）、环磷酰胺（C）和FTI R115777（Zarnestra）的假设驱动的I/II期临床试验。在此，我们将确定ErbB 1、ErbB 2、ErbB 3和/或ErbB 4的治疗前水平以及Akt、STAT 3和/或Erkl/2的磷酸化水平是否预测对AC/FTI的临床应答。我们还将临床反应与抑制蛋白法尼基化的能力和磷酸化Akt、磷酸化Erkl/2和/或磷酸化STAT 3的水平相关联。这些研究的结果将增强我们对Mek/Erk、JAK/STAT 3和PI 3 K/Akt途径在乳腺癌肿瘤发生和治疗结果中的作用的了解，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.