Abstract C13: A “mouse hospital” for preclinical testing of diagnostic and treatment modalities in pancreatic ductal adenocarcinoma (PDA)

Abstract

A major challenge for cancer drug development is deciding which compounds to bring forward to clinical trials. Mouse models provide a helpful prescreening tool, but xenograft and subcutaneous models can be poorly predictive of a treatment’s efficacy against a naturally occurring tumor. Preclinical models that more accurately reproduce all the features of a tumor, including its microenvironment, may provide a more accurate readout for response to therapy. Genetically engineered mouse (GEM) models of pancreatic ductal adenocarcinoma (PDA) have been developed that exploit the fact that virtually all PDAs exhibit activating mutations in Kras (exon 12) and that over 75% have mutations in p53. These models use a pancreas-specific Cre recombinase to create mutations in Kras and p53 in the pancreatic epithelium. Tumors in these “KPC” mice recapitulate the salient clinical, histopathologic, and molecular features of the human disease. Importantly, the tumor arises in an immune-competent host. A variant of the KPC model, known as KPCY, also has a fluorescent lineage label on pancreatic epithelial cells, permitting the evaluation of a treatment’s effects on metastatic incidence or growth. Our KPC and KPCY mice are on the C57 BL/6 strain background. Alternatively, syngeneic models provide a less labor-intensive tool for evaluating the efficacy of cancer therapies in the presence of a functional immune system. The mouse hospital employs both laparotomy and a relatively new technique of ultrasound-guided injection for orthotopic implantation of a murine PDA cell line in C57 BL/6 mice. This technique is faster, less invasive, and requires less recovery time than a traditional laparotomy. The mission of the Pancreatic Cancer Mouse Hospital of the Abramson Cancer Center is to evaluate novel PDA therapies on behalf of investigators who are at the University of Pennsylvania or are collaborating with Penn investigators. Our mouse studies are designed to mimic human clinical trials, including the use of eligibility criteria and randomized treatment assignment. Ultrasound is used for screening and to measure changes in tumor in response to therapy; serial studies permit measurement of time to diagnosis and rate of tumor progression. Additional endpoints include overall survival, serum chemistries, histology, tissue collection for pharmacodynamics studies, and immune subtyping as would be performed in a human clinical trial. Citation Format: Cynthia Clendenin, Rina Sor, Deirdre McMenamin, Ben Z. Stanger, Gregory Beatty, Robert H. Vonderheide. A “mouse hospital” for preclinical testing of diagnostic and treatment modalities in pancreatic ductal adenocarcinoma (PDA) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C13.