Abstract 1067: A patient-derived xenograft (PDX) platform for cancer translational, precision medicine and health disparity research

Abstract

Abstract Introduction and Objective: This purpose of this program is to develop and characterize PDXs from multiple organ sites and patients of multiple ethnic backgrounds, and to make these resources available to the scientific community for translational, precision medicine, and health disparity research. Methods: PDXs were directly developed from patient cancer specimens, molecularly characterized with next-generation sequencing, and annotated with clinical information. Various aspects of its applications were tested. Results: UC Davis, working in collaboration with The Jackson Laboratory (JAX), has developed PDX models, reflecting a wide range of tumor types, from 150 of our patients. Each of these models is annotated with clinical and genomic information. The fidelity of these PDXs was validated by the retention of histopathological features and the conservation of genetic aberrations (i.e., 92-97%) of the original patient tumors in bladder cancer PDXs tested. Extensive preclinical studies showed that these PDXs could potentially be used to screen multiple therapeutic agents simultaneously to identify the most efficacious drugs or drug combinations, re-purpose FDA-approved drugs, decipher the mechanisms of primary resistance, decrypt the mechanisms of secondary resistance, guide drug development, and identify biomarkers. For drug repurposing, the EGFR/ERBB2 dual inhibitor lapatinib effectively prolonged the overall survival (OS) of mice carrying ERBB2+ bladder cancer PDXs from 18.4 days to 25.4 days (p=0.007). For screening of targeted therapy in a PDX carrying PI3K, ERBB2 and Src alterations, only a PI3K inhibitor (BEZ235) prolonged the OS (p<0.0001) while lapatinib and a Src inhibitor ponatinib had no effect. For biomarker development, DNA adduct levels correlated with cancer response to alkylating agents and this project has already been translated into a clinical trial. For determination of the mechanisms of secondary resistance, loss of tumor suppressor gene LSP1 expression was associated with secondary resistance to an inhibitor of the PI3K pathway which is commonly mutated in many cancers. With the support of the Minority PDX Development and Trial Center (M-PDTC) U54 grant, UC Davis will continue to establish over 200 PDX models from bladder, lung squamous cell, gastric and hepatocellular carcinoma, with >60% of the specimens coming from minority patients, for health disparity research. Conclusions: PDXs have great potential for cancer translational, precision medicine and health disparity research. The NCI-funded U54 center with minority PDXs is open for collaboration through the PDX Development and Trial Centers Research Network (PDXNet). Citation Format: Chong-Xian Pan, Hongyong Zhang, Ai-Hong Ma, Shuxiong Zeng, Maike Zimmermann, Clifford Tepper, Paul Henderson, Luis Carvajal-Carmona, Regina Gandour-Edwards, Moon Chen, Susan Airhart, Ralph de Vere Whtie. A patient-derived xenograft (PDX) platform for cancer translational, precision medicine and health disparity research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1067.