Abstract B035: Evaluation of a novel monoclonal antibody targeting ASC amino acid transporter 2 using patient-derived xenograft mouse models of gastric cancer

Abstract

Abstract Introduction: Gastric cancer is a leading cause of global cancer mortality with an overall 5-year survival rate of approximately 20% and is particularly prevalent in many Asian countries. ASC amino acid transporter 2 (ASCT2), also known as SLC1A5, is a Na+-dependent glutamine/neutral amino acid transporter. ASCT2 acts as a high-affinity transporter of L-glutamine (Gln) and has been reported to be upregulated in a variety of cancerous tissues, including stomach. Several studies have shown that glutamine is a major nutrient contributing to cancer cell growth, so the glutamine metabolism pathway is an attractive target for gastric cancer treatment. In this study, we evaluated the efficacy of a novel anti-ASCT2 humanized monoclonal antibody, KM8094, as a therapeutic agent against gastric cancer and explored predictive biomarker candidates using patient-derived xenograft (PDX) mouse models. Materials and Methods: The tumor tissues from which the PDX models were generated were provided by Dr. Chan Shing Leng (NUS, Singapore). For the glutamine uptake assay, PDX-tumor cells were incubated with 3H-glutamine in the presence of KM8094. Intracellular 3H-glutamine was measured by liquid scintillation spectrophotometry. In vitro ADCC activity against human gastric cancer cells (SNU-16) was evaluated using human peripheral blood mononuclear cells (PBMC) from either gastric cancer patients or healthy controls as effector cells. In vivo antitumor activity of KM8094 was examined using PDX models. Mice were treated with KM8094 at 10 mg/kg i.v. or phosphate-buffered saline once weekly for 2-3 weeks. Finally, omics analyses of PDX tumor tissues were performed via a gene expression array analysis, DNA methylation array analysis, and metabolomics analysis. Results: All five gastric cancer PDX models histologically expressed ASCT2. KM8094 significantly inhibited the 3H-glutamine uptake in vitro and showed in vivo antitumor efficacy in the gastric cancer PDX models. In addition, KM8094 showed in vitro ADCC activity against gastric cancer cells using PBMCs from gastric cancer patients. These results indicated that KM8094 is a potential new therapeutic agent for gastric cancer treatment. Finally, we explored predictive biomarker candidates of KM8094 by a multi-omics analysis on the PDX models, and a few candidates were selected by genomic analyses. In addition, a metabolomics analysis revealed clear differences in the intracellular energy and redox status between responsive and nonresponsive PDX models. Conclusions: These results demonstrated the therapeutic potential of KM8094 for the treatment of gastric cancer and provide some insight into predictive biomarker candidates for antitumor efficacy. Citation Format: Noriyuki Kasai, Aya Sasakawa, Kenta Hosomi, Tze Wei Poh, Bernadette Lynn Chua, Wei Peng Yong, Jimmy So, Shing Leng Chan, Richie Soong, Koji Kono, Toshihiko Ishii, Kazuya Yamano. Evaluation of a novel monoclonal antibody targeting ASC amino acid transporter 2 using patient-derived xenograft mouse models of gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B035.