Genetic Mechanisms in Experimental Pancreatic Cancer

实验性胰腺癌的遗传机制

• 批准号: 6870021
• 负责人: ERIC P SANDGREN
• 金额: $ 27.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870021
• 关键词: Genetic; Mechanisms; Experimental; Pancreatic; Cancer

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.

描述（由申请人提供）：本申请要求对一个旨在研究外分泌胰腺癌（最致命的人类肿瘤之一）发生和发展的遗传机制的项目进行竞争性更新。该项目的主要目的是将特定遗传改变（癌基因激活、肿瘤抑制基因丢失）的存在与小鼠胰腺导管上皮细胞中的特定表型变化等同起来;迄今为止，还不可能选择性靶向这种细胞类型。这是使用基因工程小鼠模型完成的。为了提供与人类疾病的相关性，评价的遗传改变是在人类胰腺癌中最常鉴定的那些。最后，表型表征检查具有直接临床相关性的终点--病变潜伏期、多样性、组织型和行为，例如，侵袭和转移。这种方法很重要，因为癌症是一种仅在患者（动物或人）中的临床疾病，其中复杂的生长调节稳态机制是活跃的。因此，一旦在分子水平上对患者的癌症进行了评估，临床终点就提供了做出关于患者预后和治疗的决定所需的信息。这项建议的目的如下。具体目标1：建立原发性胰腺导管癌的小鼠模型。工作假设：当突变型Kras在小鼠胰腺导管上皮中表达时，发展的胰腺病变将是原位浸润前导管癌，反映了突变型Kras在胰腺癌发展的早期阶段中的作用。具体目标2：确定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Smad 4缺失协同作用，加速胰腺导管癌进展;（2）突变型Kras诱导的胰腺导管病变的维持需要持续的ras表达。具体目标3：确定erbB 2过表达和胰腺癌之间的因果关系。工作假设：（1）erbB 2在胰腺导管上皮中的过表达不足以诱导胰腺瘤形成，但是（2）它将与其它遗传改变的子集-突变Kras的表达，p53，p16的缺失， 和/或Smad 4-加速胰腺癌的发生。