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

描述(申请人提供)：胰腺癌(PDAC)是西方世界癌症死亡的第四大原因，是五年生存率低于5%的癌症中预后最差的。PDAC从癌前病变经过称为Panin的非侵袭性肿瘤性病变的不同阶段发展到浸润性癌。目前侵袭性PDAC的治疗，包括在化疗的基础上增加新的生物靶向治疗，对总体存活率几乎没有影响。这项R21建议的重点是更好地了解在Panin病变中发现的启动癌基因突变如何改变细胞信号通路，这些通路如何影响细胞的表型，以及靶向这些通路是否会防止早期病变发展为浸润性癌。在此背景下，我们从转基因小鼠和人类胰腺细胞中发现了新的Panin模型，在早期PanLN病变中发生了erb B激酶和STAT3的异常活性。我们将检验这样一种假设，即导致STAT3异常和结构性激活的erb B激酶过度激活是胰腺癌发生的早期事件，这些分子事件之间的协同作用导致导管内肿瘤病变(Panin)的建立，并且是这些病变发展为浸润性癌所必需的。提出了两个具体目标。(1)建立erbB激酶和STAT3激活在介导Panin致癌作用中的功能关系。为了达到这个目的，我们将确定erbB激酶信号和STAT3转录活性在介导Panin致癌特性中的作用，(2)在体内确定，通过erbB激酶和/或STAT3活性对信号的功能性阻断是否可以阻止Panin向侵袭性癌的建立和/或进展。这一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病变的建立和进展。此外，研究将评估体内抑制erbB激酶和/或STAT3是否足以防止下游分子靶点的激活，以及这些靶点的激活状态是否可以预测治疗反应。总体而言，这些研究将使用创新的模型来更好地了解PDAC的建立和发展所涉及的机制，并确定这些信息是否可以转化为使用临床相关药物进行预防或治疗。

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.