Establishment and Thorough Characterization of Xenograft (PDX) Models Derived from Patients with Pancreatic Cancer for Molecular Analyses and Chemosensitivity Testing

Diana Behrens; Ulrike Pfohl; Theresia Conrad; Michael Becker; Bernadette Brzezicha; Britta Büttner; Silvia Wagner; Cora Hallas; Rita Lawlor; Vladimir Khazak; Michael Linnebacher; Thomas Wartmann; Iduna Fichtner; Jens Hoffmann; Mathias Dahlmann; Wolfgang Walther

doi:10.3390/cancers15245753

Establishment and Thorough Characterization of Xenograft (PDX) Models Derived from Patients with Pancreatic Cancer for Molecular Analyses and Chemosensitivity Testing

Cancers (Basel). 2023 Dec 8;15(24):5753. doi: 10.3390/cancers15245753.

Authors

Diana Behrens¹, Ulrike Pfohl^{1

2}, Theresia Conrad¹, Michael Becker¹, Bernadette Brzezicha¹, Britta Büttner¹, Silvia Wagner³, Cora Hallas⁴, Rita Lawlor⁵, Vladimir Khazak⁶, Michael Linnebacher⁷, Thomas Wartmann⁸, Iduna Fichtner¹, Jens Hoffmann¹, Mathias Dahlmann¹, Wolfgang Walther^{1

9

10}

Affiliations

¹ Experimental Pharmacology and Oncology GmbH, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
² CELLphenomics GmbH, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
³ Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, 72076 Tübingen, Germany.
⁴ Institut für Hämatopathologie, Fangdieckstr. 75, 22547 Hamburg, Germany.
⁵ ARC-Net Research Center, University and Hospital Trust of Verona, Piazzale A. Scuro 10, 37134 Verona, Italy.
⁶ NexusPharma, 17 Black Forest Rd., Hamilton, NJ 08691, USA.
⁷ Clinic of General Surgery, Molecular Oncology and Immunotherapy, University Medical Center Rostock, 18057 Rostock, Germany.
⁸ University Clinic for General, Visceral, Vascular and Transplantation Surgery, Faculty of Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
⁹ Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Lindenberger Weg 80, 13125 Berlin, Germany.
¹⁰ Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany.

Abstract

Patient-derived xenograft (PDX) tumor models are essential for identifying new biomarkers, signaling pathways and novel targets, to better define key factors of therapy response and resistance mechanisms. Therefore, this study aimed at establishing pancreas carcinoma (PC) PDX models with thorough molecular characterization, and the identification of signatures defining responsiveness toward drug treatment. In total, 45 PC-PDXs were generated from 120 patient tumor specimens and the identity of PDX and corresponding patient tumors was validated. The majority of engrafted PDX models represent ductal adenocarcinomas (PDAC). The PDX growth characteristics were assessed, with great variations in doubling times (4 to 32 days). The mutational analyses revealed an individual mutational profile of the PDXs, predominantly showing alterations in the genes encoding KRAS, TP53, FAT1, KMT2D, MUC4, RNF213, ATR, MUC16, GNAS, RANBP2 and CDKN2A. Sensitivity of PDX toward standard of care (SoC) drugs gemcitabine, 5-fluorouracil, oxaliplatin and abraxane, and combinations thereof, revealed PDX models with sensitivity and resistance toward these treatments. We performed correlation analyses of drug sensitivity of these PDX models and their molecular profile to identify signatures for response and resistance. This study strongly supports the importance and value of PDX models for improvement in therapies of PC.

Keywords: PDX models; in vivo chemosensitivity testing; molecular profiling; pancreas carcinoma.

Grants and funding

This work was partially supported by the European Union under the seventh framework programme: Integrative Analysis of Gene Functions in Cellular and Animal Models of Pancreatic Cancer (CAM-PaC), under grant agreement no. 602783. Further funding was received from the BMBF (PakaNostra, grant no. 0315643D) and ERA-NET EuroTransBio (MetaDIC, grant no. 031B0093A).