IGF::OT::IGF PREVENT EFFICACY: OPTIMIZATION OF GEM MODELS FOR HIGH-RISK COHORTS OF HUMAN PANCREATIC CYSTADENOMAS, IPMNS, AND PANINS PROGRESSION TO PDAC.

IGF::OT::IGF 预防功效：针对人类胰腺囊腺瘤、IPMNS 和 Panins 进展至 PDAC 高风险群体的 GEM 模型的优化。

• 批准号: 9152469
• 负责人: CHINTHALAPALLY RAO
• 金额: $ 59.94万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2017-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152469
• 关键词: Adult; Apoptosis; Biological Markers; Breeding; Cancerous; Cell Proliferation; Chemoprevention; Chemopreventive Agent; Clinical Trials; Contracts; Cystadenoma; Data; Development; Embryonic Development; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Gefitinib; Genetic Crosses; Genetically Engineered Mouse; Histologic; Housing; Human; Incidence; Lesion; Malignant neoplasm of pancreas; Modeling; Molecular; Mouse Strains; Mutate; Mutation; Pancreas; Pancreatic Cystadenoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Patients; Premalignant; Risk Factors; Serum; Signal Transduction; Transgenic Mice; Translating; Writing; cohort; cytokine; high risk; inhibitor/antagonist; mouse model; neoplastic; neoplastic cell; pancreatic neoplasm; pre-clinical; prevent; receptor; tumor; tumor growth

Several Genetically Engineered Mouse (GEM) models are available which mimic some or all of the features for pancreatic ductal adenocarcinoma (PDAC) development. However, due to varied molecular features in different models, selecting the appropriate model is challenging and critical information on incidence rates, tumor multiplicity, and rate of progression for chemoprevention studies is needed. In humans, pancreatic precursor lesion development and progression occurs in the adult pancreas whereas a number of GEM models involve activation of mutated driver mutations during late embryonic development. Induction of precancerous and cancerous pancreatic lesions in these models usually occurs in the absence of pancreatitis. However, pancreatitis appears to be an important risk factor for PDAC in human patients. Hence, optimizing mouse models that represent high-risk cohorts of pancreatic cancer subjects who will participate in human chemoprevention trials will be important for translating preclinical chemopreventive observations to human clinical trials. The overall objective of this task order is to determine and characterize the temporal development of neoplastic pancreatic lesions in the genetically engineered mouse (GEM) Pdx1Cre/LSL-KrasG12D;Tif1γflox/flox model for IPMN formation and Ela-CreERT;CAG-lox-KrasG12v model for cystadenomas, pancreatitis and PanIN formation and their progression to pancreatic ductal adenocarcinoma (PDAC). These models will be optimized for use in preclinical chemoprevention studies.

几种基因工程小鼠（GEM）模型可以模拟胰腺导管腺癌（PDAC）发展的部分或全部特征。然而，由于不同模型的分子特征不同，选择合适的模型是具有挑战性的，并且需要关于发病率、肿瘤多样性和化学预防研究进展速度的关键信息。在人类中，胰腺前体病变的发展和进展发生在成人胰腺中，而许多GEM模型涉及胚胎发育晚期突变驱动突变的激活。在这些模型中，诱导癌前病变和癌性胰腺病变通常发生在没有胰腺炎的情况下。然而，胰腺炎似乎是人类患者PDAC的一个重要危险因素。因此，优化参与人类化学预防试验的胰腺癌高危人群的小鼠模型对于将临床前化学预防观察结果转化为人类临床试验至关重要。本任务顺序的总体目标是确定和表征基因工程小鼠（GEM） Pdx1Cre/LSL-KrasG12D肿瘤胰腺病变的时间发展；IPMN形成的Tif1γflox/flox模型及Ela-CreERTCAG-lox-KrasG12v模型对囊腺瘤、胰腺炎和PanIN形成及其进展为胰腺导管腺癌（PDAC）的影响。这些模型将被优化用于临床前化学预防研究。