Abstract A006: Preclinical models from rare aggressive tumors: Establishment, drug sensitivity and genomic analyses of mesothelioma PDX as models for oncology drug development

Abstract

Abstract Malignant mesothelioma is a rare but aggressive disease with few therapeutic options and a poor prognosis. The main cause of the disease is the exposition to asbestos, even after 50 years of latency. Intended therapeutic goals, such as increase of patient survival and improvement of quality of life have only been achieved to a limited extent. Curative treatment is currently still not possible. Therefore, there is a strong clinical need for translational models. For this, we have characterized patient-derived xenograft models (PDX) of mesothelioma to evaluate their suitability for preclinical research. For PDX establishment, tumor tissue from surgically resected pleura or peritoneum mesotheliomas, was implanted subcutaneously into immunodeficient mice and serially passaged for at least 3 in vivo-passages. Established PDX models were characterized towards sensitivity to standard of care drugs. PDX tissue was collected for RNA sequencing and immunohistochemistry. The generated molecular profiles (comparative gene expression and sequence variations) of the models were analyzed comprehensively. A panel of 6 mesothelioma PDX has been established. In these PDX models, characteristic histological structure of the original patient tumor was preserved. The PDX models responded individually to standard of care drugs like pemetrexed, cisplatin, and gemcitabine as well as combinations thereof. The combination of pemetrexed or gemcitabine with cisplatin showed a stronger tumor growth inhibition than the respective monotherapies. The analyzed mutational and gene expression landscape resembles the known pattern of mesotheliomas. In summary, our established mesothelioma PDX will serve as a preclinical tool to investigate cellular and molecular mechanisms of drug sensitivity and resistance. They will provide a valuable preclinical model system to identify and validate biomarkers and to develop new therapeutic approaches. Citation Format: Michael Becker, Bernadette Brzezicha, Jana Rolff, Theresia Conrad, Beate Rau, Wolfgang Walther, Jens Hoffmann. Preclinical models from rare aggressive tumors: Establishment, drug sensitivity and genomic analyses of mesothelioma PDX as models for oncology drug development [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 A006. doi:10.1158/1535-7163.TARG-19-A006