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Effect of sulfasalazine (SSZ) on cancer stem-like cells (CSCs) via inhibiting xCT signal pathway: Phase 1 study in patients with gastric cancer (EPOC 1205).
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Background: 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. 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 was conducted to determine the optimal dose. SSZ was given fourth-daily oral administration with 2 weeks as one cycle. 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, 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. Patients with high CD44v expression patientss achieved reduced expression of CD44v after the administration of SSZ for 2 weeks as well as decreased level of GSH. 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 migh be 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.
Abstracts by Kohei Shitara:
Combined analysis of three randomized phase III trials comparing S-1 monotherapy and S-1 combination therapy for first-line treatment of advanced gastric cancer.Meeting: 2017 Gastrointestinal Cancers Symposium | Abstract No: 49
A randomized, double-blind, placebo-controlled phase III study of cisplatin plus a fluoropyrimidine with or without ramucirumab as first-line therapy in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (RAINFALL, NCT02314117).Meeting: 2016 Gastrointestinal Cancers Symposium | Abstract No: TPS178
Clinicopathological features of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) in Japanese patients.Meeting: 2016 Gastrointestinal Cancers Symposium | Abstract No: 629