Abstract A014: Gastric cancer PDX models for predictive preclinical studies: Establishment, drug sensitivity, and genomic characterization

Abstract

Abstract Gastric cancer is a common malignant disease representing the fifth common cancer worldwide. Its prognosis is determined by the stage and localization (distal vs. proximal), making gastric cancer the third most lethal cancer type. In early and localized stages, the therapeutic aim is curative, in metastatic stages however, palliative treatment is the only option. Despite some progress in the last 10 years, mortality for late stage gastric cancer is still high due to late diagnosis of the disease. Therefore, we have established patient-derived xenograft models (PDX) of gastric cancer to determine their potential as a preclinical tool to improve diagnosis and therapies of this cancer. For PDX generation, tumor tissue specimens were collected from the gastric cancers immediately after surgery and transplanted subcutaneously into immunodeficient mice. Each PDX was serially passaged for at least three times. Established PDX models were treated in monotherapy with standard of care drugs, inter alia, from the European FLOT standard (5-FU, leucovorine, oxaliplatin and docetaxel). PDX tumor tissue was collected for immunohistochemistry as well as for next generation RNA sequencing and a comprehensive transcriptome analysis was performed. We established 7 new PDX models of gastric cancer and stably expanded them for further analyses. The histology of the primary tumor was preserved in the PDX model proven by histopathological evaluation. Treatment with standard of care drugs such as 5-FU, docetaxel, or oxaliplatin showed an individual response towards these drugs. The mutational and gene expression landscape of the PDX models resembles the pattern known from public gastric cancer data sets. In conclusion, the newly established gastric cancer PDX panel represents a tool for preclinical analyses of molecular mechanisms of drug sensitivity and resistance. They further provide a clinically relevant platform to identify new biomarkers and to develop novel therapies. Citation Format: Michael Becker, Bernadette Brzezicha, Theresia Conrad, Jana Rolff, Michael Linnebacher, Christoph Treese, Beate Rau, Wolfgang Walther, Jens Hoffmann. Gastric cancer PDX models for predictive preclinical studies: Establishment, drug sensitivity, and genomic characterization [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A014. doi:10.1158/1535-7163.TARG-19-A014