Abstract
Abstract Introduction: Glutamine is the most abundant amino acid in blood, serving as a major biosynthetic substrate in nucleic acids and proteins. Recent studies have shown that glutamine contributes to cancer cell proliferation, invasion, and metastasis, so targeting the glutamine pathway is expected to be a feasible approach to cancer treatment. In cancer cells, the Na+-dependent neutral amino acid exchanger alanine-serine-cysteine (ASC) transporter 2 (ASCT2) plays a key role in the glutamine uptake. ASCT2 has been shown to be overexpressed in a variety of cancerous tissues, including gastric cancer. In this study, we established a defucosylated humanized anti-human ASCT2 monoclonal antibody, KM8094, that specifically binds to the natural configuration of an extracellular domain of ASCT2. We further evaluated the efficacy of KM8094 as a therapeutic agent for gastric cancer treatment using gastric cancer cell lines. Materials and Methods: Immunohistochemistry was conducted on tumor tissue specimens. The ASCT2 expression on tumor cell-surface was analyzed by flow cytometry using KM8094 and PE-conjugated anti-human IgG monoclonal antibody. The glutamine uptake in human gastric cancer cells (SNU-16) was examined using 14C-labeled glutamine. Cell growth was measured by a CellTiter-Glo Luminescent Cell Viability Assay after 72-h treatment with KM8094 or control IgG. The in vivo anti-tumor activity of KM8094 combined with docetaxel was examined using gastric cancer xenograft models. Results: In the immunohistochemical analysis, we observed the high expression of ASCT2 in human tumor tissues, including gastric cancer. To evaluate the inhibitory activity on the ASCT2 transporter function and tumor cell growth of KM8094, we performed a glutamine uptake assay using 14C-glutamine. As a result, KM8094 inhibited the 14C-glutamine uptake in SNU-16 gastric cancer cells expressing ASCT2. KM8094 also suppressed cell growth of multiple gastric cancer cell lines both in vitro and in vivo. These results suggested that KM8094 has therapeutic potential for gastric cancer by inhibiting ASCT2 transporter activity. Furthermore, in an SNU-16 gastric cancer xenograft model, combination therapy of KM8094 and docetaxel, a therapeutic drug for gastric cancer, showed a more potent antitumor effect than either agent alone. Conclusions: KM8094 may be a potential new therapeutic agent for gastric cancer expressing ASCT2, as it exhibited antitumor growth activities both in vitro and in vivo. Citation Format: Aya Sasakawa, Kenta Hosomi, Toshihiko Ishii, Hiroshi Ando, Masayo Suzuki, Minami Imaizumi, Jian Zou, Noriyuki Kasai, Kazuya Yamano, Kazuyasu Nakamura, Ryuichiro Nakai. The establishment and evaluation of anti-ASC amino acid transporter 2 (ASCT2) antibody as a novel therapeutic antibody for 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 B037.
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