Abstract 211: Sulfasalazine (SSZ) works cancer stem-like cells (CSCs) via inhibiting xCT signal pathway: Phase 1 study in patients with gastric cancer (EPOC 1205)
Authors: Shitara Kohei , Takahashi Shunji , Nakajima Takako , Shuichi Hironaka , Nagano Osamu , Imamura Chiyo , Mushiroda Taisei , Einaga Yasuaki , Fukunani Miki , Sato Akihiro , Ohtsu Atsushi , Saya Hideyuki , Doi Toshihiko 
Published: May 2015

Back ground: CD44 is an adhesion molecule expressed in cancer stem-like cells (CSCs). Our group recently reported that CD44 splice variant (CD44v) is expressed in CSCs and interacts with xCT, a glutamate-cystine transporter, keeping high levels of the intracellular reduced glutathione (GSH). Thus, CSCs with a high expression of CD44v have an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS), resulting in resistance to various therapeutic stresses (Cancer Cell 2011; Cancer Res 2013). Sulfasalazine (SSZ) as an xCT inhibitor suppressed CD44v-dependent tumor growth and increased sensitivity to cytotoxic drugs in vivo study.

Methods: A phase 1 dose escalation study in patients with advanced gastric cancer who had received one or more standard chemotherapies was conducted to determine the optimal dose, change in CD44v expression and intra-tumor level of GSH pre- and post SSZ exposure and pharmacokinetics. SSZ was given fourth-daily oral administration with 2 weeks as one cycle, which were continued until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. A 3+3 escalation was used to evaluate a MTD. Tumor tissues were obtained pre- and post SSZ administration to evaluate expression of CD44v and intra-tumor level of GSH by immunohistochemistry and boron doped diamond microelectrode (Sci Rep 2012), respectively.

Results: Eleven patients were dosed from 8 g to 12 g/day; median age: 71 years (61-78); median number of prior chemotherapies: 3 (1-4). There was two DLT of grade 3 anorexia and nausea among patients who were treated with 12 g/day. One additional patients required frequent dose interruption with grade 2 anorexia and nausea. Therefore 12g/day was judged as MTD. No DLT was observed among patients with 8g/day. Among the 5 patients with high CD44v expression, 4 patients achieved reduced expression of CD44v after the administration of SSZ for 2 weeks. GSH was also apparently decreased in 2 of 5 patients. Further exploratory biomarker analyses are still ongoing. The individual variability of SSZ exposure was explainable in terms of the genotypes of ABCG2 and NAT2 which influence SSZ pharmacokinetics.

Conclusions: Optimal dose of SSZ was considered as 8g/day. Down regulation of CD44v expression and decreased level of GSH is confirmed as a pharmacodynamic marker of drug-on-target effect and mode of action of SSZ for CSCs, which warrants further investigation for combination with chemotherapy or other targeting agents. Clinical trial information: UMIN000010254

Citation Format: Kohei Shitara, Shunji Takahashi, Takako Nakajima, Hironaka Shuichi, Osamu Nagano, Chiyo Imamura, Taisei Mushiroda, Yasuaki Einaga, Miki Fukunani, Akihiro Sato, Atsushi Ohtsu, Hideyuki Saya, Toshihiko Doi. Sulfasalazine (SSZ) works cancer stem-like cells (CSCs) via inhibiting xCT signal pathway: Phase 1 study in patients with gastric cancer (EPOC 1205). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 211. doi:10.1158/1538-7445.AM2014-211