Genetic Mechanisms in Experimental Pancreatic Cancer

描述（由申请人提供）：本申请要求竞争性更新一个旨在研究外分泌胰腺癌（人类最致命的肿瘤之一）发生和发展的遗传机制的项目。该项目的主要目的是将小鼠胰腺导管上皮细胞中特定遗传改变（癌基因激活，肿瘤抑制基因丢失）的存在与特定表型变化等同起来；到目前为止，还不可能有选择地靶向这种细胞类型。这是通过基因工程小鼠模型完成的。为了提供与人类疾病的相关性，所评估的遗传改变是在人类胰腺癌中最常发现的。最后，表型表征检查与临床直接相关的终点——病变潜伏期、多样性、组织型和行为，例如侵袭性和转移。这种方法很重要，因为癌症是一种临床疾病，只有在患者（动物或人类）的情况下，复杂的生长调节稳态机制才活跃。因此，一旦在分子水平上对患者的癌症进行了评估，临床终点就提供了决定患者预后和治疗所需的信息。本建议有以下目的。特异性目的1：建立原发性胰腺导管癌小鼠模型。工作假设：当Kras突变体在小鼠胰腺导管上皮中表达时，发生的胰腺病变将是浸润前原位导管癌，这反映了Kras突变体在胰腺癌发展的早期阶段的作用。特异性目标2：建立Kras突变与胰腺癌发生、持续和进展之间的关系。工作假设：(1)Kras突变将与p53、p16和/或Smad4缺失协同作用，加速导管性胰腺癌的进展；(2)维持突变的kras诱导的胰腺导管病变需要持续的ras表达。特异性目的3：明确erbB2过表达与胰腺癌之间的因果关系。工作假设：(1)erbB2在胰腺导管上皮中的过度表达不足以诱导胰腺肿瘤，但(2)它会与其他基因改变的子集协同作用-突变Kras的表达，p53， p16的缺失，

DESCRIPTION (provided by applicant): This application requests competitive renewal of a project designed to examine genetic mechanisms underlying the initiation and progression of exocrine pancreatic cancer, one of the most lethal of human neoplasms. The principal objective in this project is to equate the presence of specific genetic alterations (oncogene activation, tumor suppressor gene loss) with specific phenotypic changes in mouse pancreatic ductal epithelial cells; heretofore it has not been possible to selectively target this cell type. This is accomplished using genetically engineered mouse models. To provide relevance to the human disease, the evaluated genetic alterations are those most often identified in human pancreatic cancers. Finally, phenotypic characterization examines endpoints that are of direct clinical relevance--lesion latency, multiplicity, histotype, and behavior, e.g., invasiveness and metastasis. This approach is important because cancer is a clinical disease only in the context of a patient (animal or human), in which complex growth-regulatory homeostatic mechanisms are active. Clinical endpoints, therefore, provide the information needed to make decisions about patient prognosis and treatment once that patient's cancer has been evaluated at the molecular level. This proposal has the following Aims. Specific Aim 1: Create mouse models of primary pancreatic ductal cancer. Working hypothesis: When mutant Kras is expressed in mouse pancreatic ductal epithelium, the pancreatic lesions that develop will be preinvasive ductal carcinoma in situ, reflecting a role for mutant Kras in an early Stage of pancreatic cancer development. Specific Aim 2: Establish the relationship between Kras mutation and pancreatic cancer initiation, persistence, and progression. Working hypotheses: (1) mutations in Kras will act synergistically with loss of p53, p16, and/or Smad4 to accelerate ductal pancreatic cancer progression; and (2) maintenance of mutant Kras-induced pancreatic ductal lesions requires continued ras expression. Specific Aim 3: Define the causal link between erbB2 overexpression and pancreatic cancer. Working hypotheses: (1) erbB2 overexpression in pancreatic ductal epithelium is not sufficient to induce pancreatic neoplasia, but (2) it will act synergistically with a subset of other genetic alterations - expression of mutant Kras, loss of p53, p16, and/or Smad4 - to accelerate pancreatic carcinogenesis.