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

点击翻译按钮获取中文摘要

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.