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

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大原因，并且具有任何癌症中最差的预后，五年生存率低于5%。PDAC从瘤形成前经过称为PanIN的非侵袭性肿瘤病变的各个阶段发展为侵袭性癌。目前侵入性PDAC的治疗，包括在化疗中加入新的生物靶向治疗，对总生存率的影响很小。这项R21提案的重点是更好地了解PanIN病变中发现的致癌突变如何改变细胞信号传导通路，这些通路如何影响细胞的表型，以及靶向这些通路是否会阻止早期病变进展为浸润性癌。在这种情况下，我们发现使用来自转基因小鼠和人胰腺细胞的新PanIN模型，erbB激酶和STAT 3的异常活性发生在早期PanIN病变中。我们将测试的假设，erbB激酶的过度活跃，导致异常和组成性激活的STAT 3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，并需要这些病变的进展，浸润性癌。提出了两个具体目标。(1)建立erbB激酶和STAT 3激活在介导PanIN致瘤特性中的功能关系。在这个目标中，erbB激酶信号传导和STAT 3转录活性在介导PanIN的致瘤特性中的作用将被确定。（2）在体内确定通过erbB激酶和/或STAT 3活性的信号传导的功能性阻断是否阻止PanIN向浸润性癌的建立和/或进展。该目的将使用体内模型来确定抑制erbB激酶和STAT 3活性是否阻止PanIN病变的建立和进展。此外，研究将评估抑制erbB激酶和/或STAT 3是否足以在体内预防下游分子靶点的激活，以及这些靶点的激活状态是否是对治疗反应的预测因子。总的来说，这些研究将使用创新的模型来更好地了解PDAC的建立和进展所涉及的机制，并确定这些信息是否可以转化为使用临床相关药物的预防或治疗。

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.