Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly and clinically challenging malignancies. PDACs are notoriously aggressive, prone to rapid conversion to metastases, has remarkable desmoplastic features, and is difficult to diagnose at early stages. Thus, we are executing studies to meet the stated objectives to develop, utilize, and provide to the community several tractable preclinical PDA models for therapeutic and biomarker discovery. Our progress includes: 1) Generation and characterization of 3 relevant Cre-inducible missense p53 GEM strains in which the allele expresses wild type p53 prior to conversion. The p53aa172 inducible mutant strain has been bred with PDX-Cre and KRASG12D-lsl mice to generate animals that are similar to the KPC model, with the exception that they harbor no null allele prior to expression of p53-172. Development of PDA in these mice (KPwt-172C) is similar to that of KPC mice, except that ectopic tumors do not develop and PDA develops with shortened latency. 2) Orthotopic KPC-PDA GDA models have been established and shown to develop PDA with characteristics of the parental tumor. In addition, the metastatic rate is increased to about 70 %. This high metastatic rate makes this model ideal for evaluating therapies for metastatic disease. 3) numerous GEM PDA-derived cell cultures have been validated and banked. 4) KPC-PDA micro-tumors have been generated and their characterization is underway.
