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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma
Xi Wang, Cheng-Sheng Zhang, Xu-Yuan Dong, Yuan Hu, Bao-Jun Duan, Jun Bai, Yin-Ying Wu, Lin Fan, Xin-Hua Liao, Ye Kang, Peng Zhang, Meng-Yang Li, Jiao Xu, Zhi-Jun Mao, Hui-Tong Liu, Xiao-Long Zhang, Li-Fei Tian, En-Xiao Li
Xi Wang, Xu-Yuan Dong, Yuan Hu, Yin-Ying Wu, En-Xiao Li, Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Xi Wang, Bao-Jun Duan, Jun Bai, Department of Medical Oncology, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
Cheng-Sheng Zhang, Ye Kang, Meng-Yang Li, Jiao Xu, Department of Cancer Precision Medicine, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Cheng-Sheng Zhang, Peng Zhang, Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Lin Fan, Xin-Hua Liao, Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an 710061, Shaanxi Province, China
Zhi-Jun Mao, Xiao-Long Zhang, Li-Fei Tian, Department of General Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
Hui-Tong Liu, Department of Orthopedics, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
Author contributions: Wang X, Zhang CS, Dong XY, Duan BJ, Bai J, Wu YY and Li EX designed and coordinated the study; Wang X, Hu Y, Kang Y, Li MY, Xu J and Zhang P performed the experiments and acquired and analyzed the data; Fan L and Liao XH supervised the study design and collected the clinical sample; Wang X and Zhang CS interpreted the data and wrote the manuscript; All authors contributed to the critical revisionfor important intellectual content and provided final approval of the manuscript.
Supported by the Basic Research Project of Natural Science of Shaanxi Province, No.2020JQ-943, 2021JQ-916 and 2021JQ-914; Research Project of Chinese Society of Clinical Oncology-Sai Sheng Fund, No. Y-2020Sciclone/qn-0181; Science and Technology Support Program of Shaanxi Provincial People’s Hospital, No. 2021JY-26, 2021JY-38, 2021JY-50 and 2021BJ-13; Research Fund Project of Shaanxi Provincial People’s Hospital, No. 2021YJY-18; and China Postdoctoral Science Foundation, No. 2021M702607.
Institutional review board statement: The study was reviewed and approved by the First Affiliated Hospital of Xi’an Jiaotong University Institutional Review Board (No. XJTU1AF2019LSL-C001).
Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: En-Xiao Li, PhD, Professor, Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 West Yanta Road, Xi’an 710061, Shaanxi Province, China.
doclienxiao@sina.com
Received: December 31, 2021
Peer-review started: December 31, 2021
First decision: March 10, 2022
Revised: March 22, 2022
Accepted: May 28, 2022
Article in press: May 28, 2022
Published online: July 15, 2022
Processing time: 193 Days and 15.7 Hours
ARTICLE HIGHLIGHTS
Research background
Pancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with a poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. The tight junction protein claudin 18.2 (CLDN18.2) has been proved as a novel candidate drug target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. Due to the few data available for clinicopathological characteristics of CLDN18.2 expression in PDAC, this study was performed to evaluate CLDN18.2 expression and to determine whether it can act as a potential therapeutic target for PDAC patients.
Research motivation
Zolbetuximab is a highly potent and tumor cell-selective therapeutic antibody that directly targets the tight junction molecule CLDN18.2. Zolbetuximab is currently in clinical testing and has shown good therapeutic effect. This prompted us to consider clinical testing of zolbetuximab in PDAC. Since few data are available for clinicopathological characteristics of the expression of CLDN18.2 in PDAC, this study is part of the prefeasibility program for such clinical trials.
Research objectives
The present study designed to investigate the CLDN18.2 expression in PDAC patients, and subsequently analyze its relevance with diverse clinicopathological characteristics of PDAC, and then propose a novel target for the cancer treatment of PDAC.
Research methods
The databases, including The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive, were used to analyze the expression of the CLDN18 gene in normal pancreatic tissue and pancreatic cancer. Immunohistochemistry was used to analyze the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues. Immunostained tissues were assessed applying the histoscore and subsequently fell into two groups according to detection of any or no CLDN18.2 expression. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated.
Research results
Reports found in the searched databases showed that the gene expression of CLDN18 in pancreatic tumors was much higher than that in normal tissues. Moreover, the difference was statistically significant (P < 0.01), and there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) PDACs. Of these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, in which 32 (39.5%) cases were characterized as having strong staining intensities. Normal pancreatic tissue showed only weak immunostaining. CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic.
Research conclusions
CLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma.
Research perspectives
This study is part of the prefeasibility program for some clinical trials that applied zolbetuximab in PDAC patients.
