Abstract 1314: Molecular profiling and characterization of patient-derived human pancreatic tumor xenograft models, and application for drug discovery and preclinical development of cancer therapeutics

Abstract

Abstract A major obstacle that has hampered the development and assessment of novel anticancer therapies is the inability of the conventional xenograft models to reliably predict clinical efficacy. This is in part due the fact that the cell lines used for these studies are cultured on plastic for extensive passages and lack the human extracellular matrix component that is critical for cancer-stromal cell interactions. Models are needed which more accurately reflect tumor heterogeneity and interaction with the tumor microenvironment in order to more accurately reflect tumor complexity and predict response to therapies in the clinic. This has led to the development of models by directly engrafting cancer patient-derived tumor tissues into immunodeficient mice with the aim of retaining histopathological features and molecular characteristics of the original tumor. A vital question relating to patient-derived tumor xenografts is whether tumor characteristics are maintained during passaging. We have established a number of proprietary pancreatic cancer patient-derived xenografts. Studies were performed to molecularly characterize the xenograft models and to confirm they retain similarity to the original tumors. Original patient tumors and corresponding serial xenograft passages were examined for growth, histopathological features and protein expression, as well as genomic and tumor biomarker status. Examination of these patient-derived xenograft models demonstrated that tumor morphology is maintained upon passaging. Immunohistochemical and qPCR analysis of targets of interest showed that expression levels are consistent between tumors and xenograft passages. Although slight differences were observed in genomic profiles for some individual models after engraftment in mice, whole genome profiling by microarray and aCGH revealed that individual tumor models retain organ-specific characteristics and that xenografts remain stable throughout passaging. Core sets of significantly expressed genes and genomic aberrations were maintained, with some additional changes observed during passaging. Retention of the characteristics of the original donor tumors within the xenograft models, such as tumor architecture and molecular signatures will afford the use of models which more accurately reflect patient tumor biology. Comprehensive molecular characterization of our models was utilized to investigate differential response to our proprietary drug candidates. Expanded testing in multiple models can potentially provide important pre-clinical translational information to help guide clinical trial design regarding patient subpopulations that may be more likely to respond to therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1314. doi:1538-7445.AM2012-1314