Abstract B087: A translational platform of patient-derived xenografts (PDXs) for upper gastrointestinal cancers

Abstract Upper gastrointestinal (GI) cancers, including pancreaticobiliary and gastric malignancies, represent a significant clinical challenge due to their late diagnosis and limited treatment options. Successful translation research in this field requires preclinical models that accurately capture tumor heterogeneity and reliably predict therapeutic response. Patient-derived xenografts (PDXs) serve as a critical tool for studying tumor biology and evaluating novel therapeutic strategies. We developed a robust translational pipeline for generating PDX models from primary and metastatic upper GI tumors with a high success rate, enabling a diverse biobank of over 100 PDX models, including cholangiocarcinoma (CCA), pancreatic ductal adenocarcinoma (PDAC), gastric cancer (GC), ampullary cancer (AC), and gallbladder cancer (GBC). Comprehensive molecular profiling using next-generation sequencing and immunohistochemistry demonstrated high concordance between the PDXs and their matched patient tumor tissue. Key alterations include mutations in KRAS (G12D, G12C, G12V, etc.), BRAF V600E, defects in homologous recombination repair genes (BRCA1/2, PALB2), loss of tumor suppressors (TP53, SMAD4), and epigenetic regulators (ARID1A/2, BAP1), as well as IDH1 mutations. We also detected HER2, CLDN18.2, PD-L1, MMR deficiency, EBV positivity, as well as FGFR2 fusions and NRG1 fusions. A unique feature of this platform is the inclusion of both treatment-naïve models and those derived from treatment-resistant tumors. Longitudinal PDX models, such as matched pre- and post-FGFR inhibitor-treated CCA models, provide a powerful system for investigating resistance mechanisms and testing novel therapeutic strategies to overcome the resistance. Importantly, these PDX models exhibit high predictive value in drug response testing, closely mirroring clinical outcomes. This well-characterized PDX platform represents a valuable resource for preclinical drug development, biomarker discovery, and personalized therapy strategies in upper GI cancers. Citation Format: Daniel Sin Coscujuela. A translational platform of patient-derived xenografts (PDXs) for upper gastrointestinal cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B087.