Abstract LB-158: A human xenograft model for developing personalized targeted therapy for pancreatic cancer

Background: Effective treatment regimens for pancreatic ductal adenocarcinoma (PDAC) are currently lacking. Molecular-targeted therapies, while promising, have been ineffective likely due to the heterogeneity and redundancy of molecular signaling pathways. Identification of predictors of response to defined targeted therapies is critical for the development of effective and personalized therapies. Methods: We have established a human PDAC tumor bank and have orthotopically implanted patient tumors into the pancreas of immunocompromised mice. Clinicopathologic data has been collected for each patient's tumor. Tumors successfully propagated in mice are routinely screened for six genetic mutations commonly found in pancreatic cancer. Gene expression profiling and phospho-receptor tyrosine kinase (pRTK) arrays, cytokine arrays, and reverse phase protein arrays (RPPAs) are used to profile the activated signaling pathways in individual tumors. A unique genetic and molecular profile is then constructed for each human tumor. Ingenuity pathway analysis software (Ingenuity Systems, Inc., Redwood, CA) is being implemented to map the unique signaling network for each tumor using the genetic and molecular data. Results: To date 7 tumors have been analyzed, including 2 metastatic tumors and 5 primary adenocarcinomas. All tumors contained TP53 gene mutation, whereas 5 tumors exhibited mutated KRAS and 3 contained mutations in the SMAD4 gene. Analysis using pRTK arrays revealed universal activation of EGFR and variable activation of ErbB2/Her2, RON, Tie-2, FGF-R1 and 3, and Axl. The profile of pRTKs appeared stable upon tumor passage both in vivo and in culture. RPPAs revealed significant variation among tumors in activation for MAPK, AKT, SAPK, and p38. Additional cytokine/growth factor array analysis and gene expression profiling is currently underway. Conclusion: The establishment of an orthotopic human pancreatic cancer xenograft model allows for the systematic analysis of genetic and molecular characteristics of human tumors propagated within a relevant tumor microenvironment. This model affords the ability to assess tumor growth responses to targeted therapies currently in use for multiple malignancies and to correlate tumor response with genetic perturbations, changes in gene expression and activation of cell signaling networks. This model will be a significant step toward developing personalized targeted therapy for pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-158.