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

有几种基因工程小鼠(GEM)模型可用于模拟胰腺导管腺癌(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、肿瘤多样性和进展速度的关键信息用于化学预防研究。在人类中，胰腺前体病变的发生和进展发生在成年胰腺，而许多GEM模型涉及到胚胎发育后期突变驱动突变的激活。在这些模型中，诱发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发生PDAC的一个重要危险因素。因此，优化代表将参与人类化学预防试验的胰腺癌高危队列的小鼠模型，对于将临床前化学预防观察转化为人类临床试验将是重要的。这项任务的总体目标是确定和表征胰腺肿瘤性病变在基因工程小鼠(GEM)Pdx1Cre/Ls1-KrasG12D中的时间发展；用于IPMN形成和Ela-CreERT的Tif1Flox/Flox模型；用于囊腺瘤、胰腺炎和Panin形成的CAG-LOX-KrasG12v模型及其进展为胰腺导管腺癌。这些模型将被优化用于临床前化学预防研究。

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.