Targeted Intervention of Breast Oncogenic Pathways

乳腺致癌途径的靶向干预

• 批准号: 7081272
• 负责人: SAID M SEBTI
• 金额: $ 29.54万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-13 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7081272
• 关键词: alkyltransferase; apoptosis; athymic mouse; breast neoplasms; chemosensitizing agent; clinical research; clinical trial phase I; clinical trial phase II; combination chemotherapy; cyclophosphamide; doxorubicin; enzyme inhibitors; epidermal growth factor; human therapy evaluation; immunocytochemistry; metastasis; multidrug resistance; neoplasm /cancer chemotherapy; neoplastic transformation; oncogenes; outcomes research; paclitaxel; patient oriented research; posttranslational modifications; protein kinase; western blottings

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.

描述（由申请人提供）：该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 在乳腺肿瘤发生中的作用，并制定更有效的乳腺癌新策略治疗。受体酪氨酸激酶 ErbB2 在人类乳腺癌中过度表达，这与不良预后相关。 ErbB2 与 ErbB1(EGFR)、ErbB3 或 ErbB4 异二聚化，并刺激许多信号转导途径，导致乳腺癌中持续激活的 Akt、STAT3 和 Erk1/2。它仍然存在；然而，尚不清楚这些途径中哪一条对于维持恶性转化最重要。此外，Mek/Erk、JAK/STAT3 和 PI3K/Akt 通路对乳腺肿瘤发生和治疗结果的贡献尚不清楚。我们和其他人开发了这些信号通路的破坏者，包括 ErbB2 抗体和 ErbB1 酪氨酸激酶、Mek 和 PI3K 激酶、JAK/STAT3 信号传导和法呢基转移酶抑制剂，法呢基转移酶是激活法尼基化蛋白（如 Ras）所需的酶，可激活 Mek/Erk和 PI3K/Akt 通路。在这个项目中，我们建议测试以下假设：组成性激活的 Mek/Erk、JAK/STAT3 和/或 PI3K/Akt 通路有助于乳腺肿瘤发生和肿瘤抵抗，并且这些通路的靶向干预可阻止恶性转化、诱导细胞凋亡并使乳腺敏感。肿瘤要化疗。该假设将通过以下具体目标进行检验： 1) 研究组成型激活的 PI3K/Akt、JAK/STAT3 和 Mek/Erk 在乳腺癌肿瘤发生中的作用。在这里，我们将确定这些途径的遗传和药理学破坏是否可以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途径、PI3K、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ErbB2和/或EGFR过表达乳腺癌细胞对赫赛汀或易瑞莎的耐药性是否是由于组成型激活的Akt/PI3K、JAK/STAT3和/或MEK/Erk通路所致。为此，我们将确定这些途径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) 确定乳腺癌细胞对阿霉素、环磷酰胺和/或泰素帝的耐药性是否可以通过PI3K/Akt、Mek/Erk和/或JAK/STAT3通路的靶向药理学干预来克服。 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/lI期临床试验。在这里，我们将确定ErbB1、ErbB2、ErbB3和/或ErbB4的治疗前水平以及Akt、STAT3和/或Erk1/2的磷酸化水平是否预测对AC/FTI的临床反应。我们还将临床反应与抑制蛋白质法呢基化的能力和磷酸Akt、磷酸Erk1/2和/或磷酸STAT3的水平关联起来。这些研究的结果将增强我们对 Mek/Erk、JAK/STAT3 和 PI3K/Akt 通路在乳腺癌肿瘤发生和治疗结果中的作用的理解，并将改善人类乳腺癌的治疗。