Role of ErbB/Stat3 in the establishment and progression of pancreatic cancer

ErbB/Stat3 在胰腺癌发生和进展中的作用

• 批准号: 7422386
• 负责人: James W. Freeman
• 金额: $ 20.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-11 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7422386
• 关键词: Cancer Etiology; Carcinoma; Cells; Cessation of life; Data; Detection; Diagnosis; Disease; Event; Genetic; Human; Hyperactive behavior; In Vitro; Invasive; Laboratories; Lesion; Lesion by Stage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Molecular; Molecular Biology; Molecular Target; Mutation; Neoplasms; Oncogenic; Pancreas; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Prevention; Property; Publishing; Role; STAT3 gene; Signal Pathway; Signal Transduction; Staging; Stream; Symptoms; Testing; Transgenic Mice; Transgenic Model; Translating; Western World; carcinogenesis; chemotherapy; clinically relevant; in vivo; in vivo Model; innovation; neoplastic; novel; outcome forecast; prevent; response; tumorigenic

DESCRIPTION (provided by applicant): Pancreatic adenocarcinomas (PDAC) are the 4th leading cause of cancer deaths in the western world and have the worst prognosis of any cancer with a five-year survival of less than 5%. PDAC develops from pre-neoplasia through various stages of non-invasive neoplastic lesions called PanIN to invasive carcinoma. Current treatments of invasive PDAC including the addition of new biologically targeted therapies to chemotherapy have little impact on overall survival. This R21 proposal focuses at better understanding how initiating oncogenic mutations found in PanIN lesions alter cell signaling pathways, how these pathways influence the phenotype of the cell and whether targeting these pathways will prevent the progression of early lesions to invasive carcinoma. In this context, we found using novel PanIN models from transgenic mice and from human pancreas cells that aberrant activities of erbB kinases and STAT3 occur in early stage PanlN lesions. We will test the hypothesis that hyperactivity of erbB kinases causing aberrant and constitutive activation of STAT3 are early events in pancreatic carcinogenesis and that synergy between these molecular events leads to the establishment of intraductal neoplastic lesions (PanIN) and are required for the progression of these lesions to invasive carcinoma. Two specific aims are proposed. (1) To establish the functional relationship between erbB kinases and STAT3 activation in mediating the tumorigenic properties of PanIN. In this aim the roles of erbB kinase signaling and STAT3 transcriptional activities in mediating the tumorigenic properties of PanIN will be determined, (2) Determine in vivo, whether functional blockade of signaling by erbB kinases and/or STAT3 activity prevents the establishment and/or progression of PanIN to invasive carcinoma. This aim will use in vivo models to determine whether inhibiting erbB kinases and STAT3 activities prevent the establishment and progression of PanIN lesions. In addition, studies will assess whether inhibiting erbB kinases and/or STAT3 are sufficient in vivo for preventing the activation of down stream molecular targets and whether the activation status of these targets are predictors of response to therapy. Overall, these studies will use innovative models to provide a better understanding of the mechanisms involved in the establishment and progression of PDAC and determine whether this information can be translated to prevention or therapy using clinically relevant drugs.

描述（由申请人提供）：胰腺腺癌（PDAC）是西方世界癌症死亡的第四个主要原因，并且在任何癌症中的预后最差，五年生存率低于5％。 PDAC从偏见前通过称为Panin到浸润性癌的非侵入性肿瘤病变的各个阶段发展。当前对入侵性PDAC的治疗方法，包括在化学疗法中添加新的以生物学靶向疗法的疗法对总体生存率影响不大。该R21提案的重点是更好地理解Panin病变中发现的致癌突变如何改变细胞信号通路，这些途径如何影响细胞的表型，以及靶向这些途径是否会防止早期病变向侵袭性癌的发展。在这种情况下，我们发现使用来自转基因小鼠和人类胰腺细胞的新型PANIN模型，使ERBB激酶和STAT3的异常活性发生在PANLN PANLN病变中。我们将检验以下假设：ERBB激酶的多动症和STAT3的构成激活是胰腺癌发生的早期事件，并且这些分子事件之间的协同作用会导致建立内导膜肿瘤病变（PANIN），并且需要这些病情的进展，这些病情是这些病情的进展。提出了两个具体目标。 （1）在介导Panin的致瘤特性时，建立ERBB激酶与STAT3激活之间的功能关系。在此目标中，将确定ERBB激酶信号传导和STAT3转录活性在介导Panin的致瘤特性中的作用，（2）在体内确定，ERBB激酶和/或STAT3活性在体内确定信号传导是否会导致Panin对侵入性电脑瘤的建立和/或进展。该目标将使用体内模型来确定抑制ERBB激酶和STAT3活性是否可以阻止Panin病变的建立和发展。此外，研究将评估抑制ERBB激酶和/或STAT3是否足够在体内足以防止沿流分子靶标的激活以及这些靶标的激活状态是否是对治疗反应的预测指标。总体而言，这些研究将使用创新模型来更好地理解PDAC建立和发展的机制，并确定该信息是否可以使用临床相关药物转化为预防或治疗。