Published online Jul 15, 2022. doi: 10.4251/wjgo.v14.i7.1252
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
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.
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.
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.
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.
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.
CLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma.
This study is part of the prefeasibility program for some clinical trials that applied zolbetuximab in PDAC patients.