A primary human xenograft model of pancreatic cancer.

胰腺癌的原发性人类异种移植模型。

• 批准号: 7707987
• 负责人: TODD W BAUER
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707987
• 关键词: Automobile Driving; Behavior; Cancer Etiology; Cell Surface Receptors; Cessation of life; Characteristics; Clinical; Clinical Trials; Disease Progression; Environment; Goals; Growth; Human; Immune; Implant; Individual; Kinetics; Literature; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Molecular; Molecular Genetics; Mus; Neoplasm Metastasis; Pancreas; Patients; Pre-Clinical Model; Preclinical Testing; Process; Property; Signal Pathway; Signal Transduction; Specimen; Therapeutic Agents; Time; Transplantation; Tumor Cell Invasion; United States; Work; Xenograft Model; Xenograft procedure; base; implantation; model development; mouse model; novel; novel strategies; pancreatic neoplasm; public health relevance; receptor expression; response; tumor; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): The five-year survival for patients with pancreatic cancer is less than 5%. Several novel therapies have been shown to be highly effective in mouse models of pancreatic cancer; however, in human clinical trials these agents have failed. There is a compelling need for preclinical models of pancreatic cancer that more accurately reflect the process of disease progression in patients. The objective of this proposal is to develop an orthotopic mouse model of pancreatic cancer using primary human tumors implanted into the pancreas of immune compromised mice. A key component of this model will be the genetic and molecular characterization of tumors and correlation of this with the biologic behavior of the tumors (e.g. grade, invasiveness). The orthotopic model is based on studies described in the literature and previous work of the PI. The establishment of a robust and well characterized orthotopic model will facilitate preclinical testing on an individualized basis of therapeutic agents that target defined signaling pathways important for pancreatic cancer progression and metastasis. A central hypothesis driving the development of the model is that orthotopic implantation of primary human xenografts into the pancreas will more closely recapitulate the growth environment of human pancreatic cancers. Thus, the molecular and cellular analysis of the orthotopically implanted tumors should more accurately reflect the biologic behavior of individual patient tumors, allowing the assessment of the repertoire of cell surface receptor expression/activation and cell signaling pathways activated in each tumor. The Experimental Plan details the following two specific aims: 1) To collect human pancreatic cancer specimens then propagate tumors orthotopically in mice and evaluate growth kinetics, tumor invasion, and metastasis. 2) To perform molecular characterization of human and xenografted tumors and correlate the molecular signaling profile of each tumor with its growth, invasive, and metastatic behavior. While previous studies have described the transplantation of pancreatic tumors subcutaneously and orthotopically, the model described herein will be the first attempt to correlate the clinical properties of pancreatic tumors with the molecular and cellular properties of the tumors propagated orthotopically in the pancreas. In addition to providing fundamental information about the molecular and cellular properties of primary pancreatic cancers, development of this model will be the next step toward arriving at a personalized approach to therapy for pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and has the shortest survival time of any cancer. Our goal is to develop a novel approach to therapy for pancreatic cancer, with treatment individualized for each patient depending on the best target for therapy of their specific tumor. We plan to achieve this by developing a mouse model of pancreatic cancer in which portions of patients' tumors are grown in the mouse pancreas, and then assessed for their molecular characteristics and response to treatment.

描述（由申请人提供）：胰腺癌患者的五年生存率低于5%。几种新的治疗方法已被证明在胰腺癌的小鼠模型中非常有效;然而，在人类临床试验中，这些药物都失败了。迫切需要更准确地反映患者疾病进展过程的胰腺癌临床前模型。本提案的目的是使用植入免疫受损小鼠胰腺的原发性人类肿瘤来开发胰腺癌的原位小鼠模型。该模型的一个关键组成部分是肿瘤的遗传和分子表征及其与肿瘤生物学行为（如分级、侵袭性）的相关性。原位模型基于文献中描述的研究和PI先前的工作。建立一个强大的和良好表征的原位模型将有助于在个体化的基础上对治疗剂进行临床前测试，这些治疗剂靶向对胰腺癌进展和转移重要的定义的信号通路。驱动该模型开发的中心假设是，将原代人异种移植物原位植入胰腺将更接近地重现人胰腺癌的生长环境。因此，原位植入肿瘤的分子和细胞分析应更准确地反映个体患者肿瘤的生物学行为，从而能够评估每个肿瘤中激活的细胞表面受体表达/激活和细胞信号传导途径的库。实验计划详细说明了以下两个具体目标：1）收集人胰腺癌标本，然后在小鼠中原位增殖肿瘤，并评价生长动力学、肿瘤侵袭和转移。2)对人和异种移植肿瘤进行分子表征，并将每种肿瘤的分子信号传导特征与其生长、侵袭和转移行为相关联。虽然之前的研究已经描述了胰腺肿瘤的皮下和原位移植，但本文描述的模型将是首次尝试将胰腺肿瘤的临床特性与胰腺中原位传播的肿瘤的分子和细胞特性相关联。除了提供有关原发性胰腺癌分子和细胞特性的基本信息外，该模型的开发将是实现胰腺癌个性化治疗方法的下一步。公共卫生关系：胰腺癌是美国癌症死亡的第四大原因，并且在任何癌症中生存时间最短。我们的目标是开发一种治疗胰腺癌的新方法，根据患者特定肿瘤的最佳治疗靶点，为每位患者提供个性化治疗。我们计划通过开发一种胰腺癌小鼠模型来实现这一目标，在该模型中，患者的肿瘤部分在小鼠胰腺中生长，然后评估其分子特征和对治疗的反应。