Abstract 1964: Identification of a novel molecule target for the detection, prediction, and treatment of peritoneal metastasis of gastric cancer

Abstract

Abstract Background: Advanced gastric cancer (GC) frequently recurs because of undetected micrometastases even when disease is localized and patients undergo curative resection. Moreover, peritoneal metastasis is fatal. We aimed to develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of GC to improve management. Methods: We conducted a metastatic pathway-specific transcriptome analysis to identify candidate biomarkers comprising 340 patients allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value. The mRNA and protein levels in primary GC tissues were compared with patients’ clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. Results: Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. SYT8 levels were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. High SYT8 levels were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between high and low SYT8 levels was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. Conclusions: SYT8 expression represents a promising diagnostic and predictive biomarker for peritoneal metastasis of GC. Citation Format: Mitsuro Kanda, Haruyoshi Tanaka, Dai Shimizu, Daisuke Kobayashi, Chie Tanaka, Hideki Takami, Masamichi Hayashi, Naoki Iwata, Yukiko Niwa, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera. Identification of a novel molecule target for the detection, prediction, and treatment of peritoneal metastasis of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1964. doi:10.1158/1538-7445.AM2017-1964