The five-year survival for patients with pancreatic cancer is less than 5%. Several novel therapies have been shown to be highly effective in mouse models of pancreatic cancer;however, in human clinical trials these agents have failed. There is a compelling need for preclinical models of pancreatic cancer that more accurately reflect the process of disease progression in patients. The objective of this proposal is to develop an orthotopic mouse model of pancreatic cancer using primary human tumors implanted into the pancreas of immune compromised mice. A key component of this model will be the genetic and molecular characterization of tumors and correlation of this with the biologic behavior of the tumors (e.g. grade, invasiveness). The orthotopic model is based on studies described in the literature and previous work of the PI. The establishment of a robust and well characterized orthotopic model will facilitate preclinical testing on an individualized basis of therapeutic agents that target defined signaling pathways important for pancreatic cancer progression and metastasis. A central hypothesis driving the development of the model is that orthotopic implantation of primary human xenografts into the pancreas will more closely recapitulate the growth environment of human pancreatic cancers. Thus, the molecular and cellular analysis of the orthotopically implanted tumors should more accurately reflect the biologic behavior of individual patient tumors, allowing the assessment of the repertoire of cell surface receptor expression/activation and cell signaling pathways activated in each tumor. The Experimental Plan details the following two specific aims: 1) To collect human pancreatic cancer specimens then propagate tumors orthotopically in mice and evaluate growth kinetics, tumor invasion, and metastasis. 2) To perform molecular characterization of human and xenografted tumors and correlate the molecular signaling profile of each tumor with its growth, invasive, and metastatic behavior. While previous studies have described the transplantation of pancreatic tumors subcutaneously and orthotopically, the model described herein will be the first attempt to correlate the clinical properties of pancreatic tumors with the molecular and cellular properties of the tumors propagated orthotopically in the pancreas. In addition to providing fundamental information about the molecular and cellular properties of primary pancreatic cancers, development of this model will be the next step toward arriving at a personalized approach to therapy for pancreatic cancer.
Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and has the shortest survival time of any cancer. Our goal is to develop a novel approach to therapy for pancreatic cancer, with treatment individualized for each patient depending on the best target for therapy of their specific tumor. We plan to achieve this by developing a mouse model of pancreatic cancer in which portions of patients'tumors are grown in the mouse pancreas, and then assessed for their molecular characteristics and response to treatment.
| Walters, Dustin M; Lindberg, James M; Adair, Sara J et al. (2013) Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib. Neoplasia 15:143-55 |
| Walters, Dustin M; Stokes, Jayme B; Adair, Sara J et al. (2013) Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens. PLoS One 8:e77065 |
| Stokes, Jayme B; Adair, Sara J; Slack-Davis, Jill K et al. (2011) Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol Cancer Ther 10:2135-45 |
