Abstract 639: Subtyping of pancreatic cancer patient-derived xenograft tumors and implications for anticancer agent testing

Abstract

Abstract Despite improvements in treatment, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a continuous increase in incidence emphasizing the need for further research and therapeutic development. In recent years, we have developed a collection of >40 patient-derived xenograft (PDX) models from PDAC. In order to determine their relevance for anticancer agent testing, we extensively characterized our models for histology features, whole exome mutations (Hiseq 2000), chromosome rearrangements, gene copy number variations (Affymetrix SNP6) and gene expression (Affymetrix U133 Plus2.0). PDAC from 65 patients were implanted into immuno-compromised mice, resulting in the development of 42 PDX models (success rate 65%). The PDAC from which models were established included moderate and poorly differentiated tumors and were heterogeneous for stroma content. In patient tumors, we showed fibroblast activation but not stroma content predicted poor patient outcome (p<0.0001) and success of PDX establishment (p<0.01). Correlating with those of the parental tumors, the resulting PDAC_PDX also showed heterogeneity for stroma content and for murine fibroblast activation. As seen in patient tumors, the PDAC_PDX were characterized by frequent chromosomal instability, with 38% of the models presenting a moderate hypoploidy while the 62% remaining ones showed a hyperploidy. Two models showed hypermutation due to mismatch repair deficiency while the others had on average a lower mutation load when compared to other histotypes such as colon, lung or melanoma tumors. In total, we identified more than 9000 genes altered by homozygous deletions, high gene amplifications and/or mutations, most of the models showed alterations in KRAS (81%), TP53 (67%), CDKN2A (64%) and TGFBR2/SMAD4 (64%) genes. Next, PDAC_PDX profiles were merged with those of patient tumors to determine PDAC_PDX subtypes and were found to be of the classical (61%), quasi mesenchymal (QM) (34%) and exocrine like subtype (5%) according to the 62 gene expression signature established by Collisson et al. 2011. Preliminary biomarker analysis revealed certain associations between genomic alterations and transcriptome subtypes, such as more frequent alterations in the TGFB pathway in classical PDX (80%) compared to QM (47%). Further detailed biomarkers analyses also addressing questions of molecular determinants of stroma content, of fibroblast activation and of sensitivity toward anticancer agents will be presented. Extensive characterization of our PDAC_PDX collection revealed similarities with patient tumors with regards of histology features including stroma content and fibroblast activation. At molecular level, the models showed similar genomic and transcriptomic patterns as those reported for patient PDAC, altogether, proving the value of this collection for drug development investigations. Citation Format: Peter Bronsert, Tim Kees, Bruno Zeitouni, Anne-Lise Peille, Manuel Landesfeind, Heinz-Herbert Fiebig, Simon Kuesters, Vincent Vuaroqueaux. Subtyping of pancreatic cancer patient-derived xenograft tumors and implications for anticancer agent testing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 639.