Abstract 1037: Comprehensive molecular profiles of gastric cancer patient derived xenograft (PDX) models and its implication in precision cancer medicine

Abstract

Abstract Background: Recent cancer research is focused on precision medicine with the advent of next generation sequencing (NGS) technology and patient tumor derived model systems. Here, we present molecular characteristics of gastric cancer patient derived xenograft (PDX) models and explore the potential of molecularly defined PDX model based drug development. Materials and Methods: We generated PDX models from patient tumors with advanced gastric cancer. The genomic alterations of tumors were profiled by whole exome sequencing (WES), RNA sequencing (RNAseq), targeted sequencing, in-situ hybridization (ISH) and immunohistochemistry (IHC). Further, we developed overcoming strategy of chemotherapy resistance mechanism by combination of signaling pathway inhibitor and standard chemotherapy regimen in “N-of-1” PDX trial. Results: Thirty-five PDX models were successfully established and categorized into four subgroups of The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications: EBV (2.9%), MSI (20.6%), GS (23.5%) and CIN (52.9%) subtypes by TCGA while MSI type (11.4%), MSS/EMT type (17.1%), MSS/TP53+ (31.4%) and MSS/TP53- type (40.0%) by ACRG. In the protein levels by IHC, there were 21 cases (60.0%) of any RTK proteins overexpression; nine of HER2 (25.7%), 14 of EGFR (40.0%), and 16 of c-MET (45.7%). Five tumors (14.3%) were related to PTEN loss and 22 tumors (62.9%) showed p53 overexpression or null. Targeted sequencing identified that ERBB2 (25.7%), KRAS (11.4%), and CCND1 (11.4%) were found frequently amplified gene while PIK3CA (11.4%) and CTNNB1 (8.6%) were found most mutated genes. N-of-1 PDX trial demonstrated that the response to FOLFOX in PDX tumor was concordant with that of corresponding patient. In FOLFOX resistant tumors, multiple signaling pathways were up-regulated and inhibition of these signaling pathways was regressed tumor growth. Conclusions: The utilization of molecularly catalogued gastric cancer PDX models will guide precision medicine for cancer therapy and be a useful tool for drug development and repurposing. Citation Format: Jae Eun Lee, Yoon Young Choi, Ju Yeon Lim, Su-Jin Shin, Gunho Lee, Eun Young Kim, Taeil Son, Hyoung-Il Kim, Woo Jin Hyung, Sung Hoon Noh, Hyunki Kim, Minkyu Jung, Sangwoo Kim, Soonmyung Paik, Jae-Ho Cheong. Comprehensive molecular profiles of gastric cancer patient derived xenograft (PDX) models and its implication in precision cancer medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1037.