Research progress and prospect of Claudin 18.2 in malignant tumors_West China Medical Journal

Authors：

FAN Mi ¹ , LUO Ting ² , ZHANG Yu ³ ,  DU Xiaobo ^1,3

1. Department of Clinical Medicine, North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. Breast Disease Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
3. Department of Oncology, Mianyang Central Hospital, Mianyang, Sichuan 621000, P. R. China;

Corresponding?author：

DU Xiaobo, Email: duxiaobo2005@126.com

Keywords：

Claudin 18.2; cancer; targeted therapy

DOI：

10.7507/1002-0179.202303157

Video：

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Abstract Full text Figures/Tables Video References Cited by

In the process of solid tumor transformation, the expression of claudins is often dysregulated. Claudins are involved in almost all aspects of tumor biology and steps of tumor development, suggesting that they have the potential to be diagnostics, and prognostic biomarkers and therapeutic targets. Current studies have found that Claudin18.2 is overexpressed in gastric cancer, pancreatic cancer, ovarian cancer and other diseases. Targeted anti-tumor therapy based on Claudin 18.2 has become a research hotspot recently. Therefore, this article reviews the basic structural characteristics of Claudin18.2, its expression in various malignant solid tumors, the progress of research and application, and prospect.

Citation： FAN Mi, LUO Ting, ZHANG Yu, DU Xiaobo. Research progress and prospect of Claudin 18.2 in malignant tumors. West China Medical Journal, 2023, 38(9): 1428-1434. doi: 10.7507/1002-0179.202303157 Copy

1.	Bray F, Laversanne M, Weiderpass E, et al. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer, 2021, 127(16): 3029-3030.
2.	Qiu H, Cao S, Xu R. Cancer incidence, mortality, and burden in China: a time-trend analysis and comparison with the United States and United Kingdom based on the global epidemiological data released in 2020. Cancer Commun (Lond), 2021, 41(10): 1037-1048.
3.	Zheng RS, Zhang SW, Zeng HM, et al. Cancer incidence and mortality in China, 2016. JNCC, 2022, 2(1): 1-9.
4.	Baudino TA. Targeted cancer therapy: the next generation of cancer treatment. Curr Drug Discov Technol, 2015, 12(1): 3-20.
5.	Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol, 2018, 834: 188-196.
6.	Cao W, Xing H, Li Y, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res, 2022, 10(1): 38.
7.	Otani T, Furuse M. Tight junction structure and function revisited. Trends Cell Biol, 2020, 30(10): 805-817.
8.	Zihni C, Mills C, Matter K, et al. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol, 2016, 17(9): 564-580.
9.	Kyuno D, Takasawa A, Takasawa K, et al. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers, 2022, 10(1): 1967080.
10.	Gowrikumar S, Singh AB, Dhawan P. Role of claudin proteins in regulating cancer stem cells and chemoresistance-potential implication in disease prognosis and therapy. Int J Mol Sci, 2019, 21(1): 53.
11.	Morin PJ. Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res, 2005, 65(21): 9603-9606.
12.	Ouban A. Claudin-1 role in colon cancer: an update and a review. Histol Histopathol, 2018, 33(10): 1013-1019.
13.	Niclauss N, Gütgemann I, Dohmen J, et al. Novel biomarkers of gastric adenocarcinoma: current research and future perspectivesv. Cancers (Basel), 2021, 13(22): 5660.
14.	Cheung ST, Leung KL, Ip YC, et al. Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma. Clin Cancer Res, 2005, 11(2 Pt 1): 551-556.
15.	Luo J, Chimge NO, Zhou B, et al. CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro. Int J Cancer, 2018, 143(12): 3169-3180.
16.	Iwaya M, Hayashi H, Nakajima T, et al. Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy. Histopathology, 2021, 79(2): 227-237.
17.	Kage H, Flodby P, Zhou B, et al. Dichotomous roles of claudins as tumor promoters or suppressors: lessons from knockout mice. Cell Mol Life Sci, 2019, 76(23): 4663-4672.
18.	Shu Y, Zhang W, Hou Q, et al. Prognostic significance of frequent CLDN18-ARHGAP26/6 fusion in gastric signet-ring cell cancer. Nat Commun, 2018, 9(1): 2447.
19.	Tanaka A, Ishikawa S, Ushiku T, et al. Frequent CLDN18-ARHGAP fusion in highly metastatic diffuse-type gastric cancer with relatively early onset. Oncotarget, 2018, 9(50): 29336-29350.
20.	Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res, 2008, 14(23): 7624-7634.
21.	Yamaguchi H, Kojima T, Ito T, et al. Transcriptional control of tight junction proteins via a protein kinase C signal pathway in human telomerase reverse transcriptase-transfected human pancreatic duct epithelial cells. Am J Pathol, 2010, 177(2): 698-712.
22.	Ito T, Kojima T, Yamaguchi H, et al. Transcriptional regulation of claudin-18 via specific protein kinase C signaling pathways and modification of DNA methylation in human pancreatic cancer cells. J Cell Biochem, 2011, 112(7): 1761-1772.
23.	Fan L, Chong X, Zhao M, et al. Ultrasensitive gastric cancer circulating tumor cellular CLDN18.2 RNA detection based on a molecular beacon. Anal Chem, 2021, 93(2): 665-670.
24.	Wang S, Qi C, Ding J, et al. First-in-human CLDN18.2 functional diagnostic pet imaging of digestive system neoplasms enables whole-body target mapping and lesion detection. Eur J Nucl Med Mol Imaging, 2023, 50(9): 2802-2817.
25.	Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol, 2020, 18(3): 534-542.
26.	Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev, 2017, 8(8): CD004064.
27.	Oh DY, Bang YJ. Pertuzumab in gastrointestinal cancer. Expert Opin Biol Ther, 2016, 16(2): 243-253.
28.	Kang BW, Baek DW, Kang H, et al. Novel therapeutic approaches for epstein-barr virus associated gastric cancer. Anticancer Res, 2019, 39(8): 4003-4010.
29.	Hsu A, Chudasama R, Almhanna K, et al. Targeted therapies for gastroesophageal cancers. Ann Transl Med, 2020, 8(17): 1104.
30.	Baek JH, Park DJ, Kim GY, et al. Clinical implications of Claudin18.2 expression in patients with gastric cancer. Anticancer Res, 2019, 39(12): 6973-6979.
31.	Niu Q, Liu JM, Luo XX, et al. Future of targeted therapy for gastrointestinal cancer: Claudin 18.2. Oncol Transl Med, 2021, 7(3): 102-107.
32.	Rohde C, Yamaguchi R, Mukhina S, et al. Comparison of Claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol, 2019, 49(9): 870-876.
33.	Hong JY, An JY, Lee J, et al. Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer. Transl Cancer Res, 2020, 9(5): 3367-3374.
34.	Dottermusch M, Krüger S, Behrens HM, et al. Expression of the potential therapeutic target Claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Arch, 2019, 475(5): 563-571.
35.	Weng W, Zhang M, Ni S, et al. Decreased expression of Claudin-18. 2 in alpha-fetoprotein-producing gastric cancer compared to conventional gastric cancer. J Gastrointest Oncol, 2022, 13(3): 1035-1045.
36.	Ungureanu BS, Lungulescu CV, Pirici D, et al. Clinicopathologic relevance of Claudin 18.2 expression in gastric cancer: a meta-analysis. Front Oncol, 2021, 11: 643872.
37.	Moentenich V, Gebauer F, Comut E, et al. Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies. Oncol Lett, 2020, 19(6): 3665-3670.
38.	Sahin U, Schuler M, Richly H, et al. A phase Ⅰ dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer. Eur J Cancer, 2018, 100: 17-26.
39.	Singh P, Toom S, Huang Y. Anti-Claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. J Hematol Oncol, 2017, 10(1): 105.
40.	Sahin U, Al-Batran SE, Hozaeel W, et al. IMAB362 plus zoledronic acid (ZA) and interleukin-2 (IL-2) in patients (pts) with advanced gastroesophageal cancer (GEC): clinical activity and safety data from the PILOT phaseⅠtrial. J Clin Oncol, 2015, 33(Suppl 15): e15079.
41.	Türeci O, Sahin U, Schulze-Bergkamen H, et al. A multicentre, phase Ⅱa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann Oncol, 2019, 30(9): 1487-1495.
42.	Sahin U, Türeci ?, Manikhas G, et al. FAST: a randomised phase Ⅱ study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced Claudin18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol, 2021, 32(5): 609-619.
43.	Teng F, Gu Y, Chai H, et al. Abstract 5183: the preclinical characterization of TST001, a novel humanized anti-Claudin18.2 mAb with enhanced binding affinity and anti-tumor activity. Cancer Res, 2020, 80(Suppl 16): 5183.
44.	Jiang H, Shi Z, Wang P, et al. Claudin18.2-specific chimeric antigen receptor engineered T cells for the treatment of gastric cancer. J Natl Cancer Inst, 2019, 111(4): 409-418.
45.	Qi C, Gong J, Li J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med, 2022, 28(6): 1189-1198.
46.	Zhu G, Foletti D, Liu X, et al. Targeting CLDN18.2 by CD3 bispecific and ADC modalities for the treatments of gastric and pancreatic cancer. Sci Rep, 2019, 9(1): 8420.
47.	McGuigan A, Kelly P, Turkington RC, et al. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol, 2018, 24(43): 4846-4861.
48.	Cai J, Chen H, Lu M, et al. Advances in the epidemiology of pancreatic cancer: trends, risk factors, screening, and prognosis. Cancer Lett, 2021, 520: 1-11.
49.	Ghosn M, Kourie HR, El Rassy E, et al. Where does chemotherapy stands in the treatment of ampullary carcinoma? A review of literature. World J Gastrointest Oncol, 2016, 8(10): 745-750.
50.	Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet, 2011, 378(9791): 607-620.
51.	Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med, 2011, 364(19): 1817-1825.
52.	Basturk O, Khayyata S, Klimstra DS, et al. Preferential expression of MUC6 in oncocytic and pancreatobiliary types of intraductal papillary neoplasms highlights a pyloropancreatic pathway, distinct from the intestinal pathway, in pancreatic carcinogenesis. Am J Surg Pathol, 2010, 34(3): 364-370.
53.	W?ll S, Schlitter AM, Dhaene K, et al. Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Int J Cancer, 2014, 134(3): 731-739.
54.	Türeci ?, Mitnacht-Kraus R, W?ll S, et al. Characterization of zolbetuximab in pancreatic cancer models. Oncoimmunology, 2018, 8(1): e1523096.
55.	Zhan Xianbao, Wang Bin, Li Zonghai, et al. PhaseⅠtrial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma. J Clin Oncol, 2019, 37(Suppl 15): 2509.
56.	Matsuda M, Sentani K, Noguchi T, et al. Immunohistochemical analysis of colorectal cancer with gastric phenotype: Claudin-18 is associated with poor prognosis. Pathol Int, 2010, 60(10): 673-680.
57.	Relli V, Trerotola M, Guerra E, et al. Abandoning the notion of non-small cell lung cancer. Trends Mol Med, 2019, 25(7): 585-594.
58.	Micke P, Mattsson JS, Edlund K, et al. Aberrantly activated Claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer. Int J Cancer, 2014, 135(9): 2206-2214.
59.	T?kés AM, Szász AM, Juhász E, et al. Expression of tight junction molecules in breast carcinomas analysed by array PCR and immunohistochemistry. Pathol Oncol Res, 2012, 18(3): 593-606.
60.	Arnold A, Daum S, von Winterfeld M, et al. Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas. Clin Transl Oncol, 2020, 22(12): 2357-2363.

1. Bray F, Laversanne M, Weiderpass E, et al. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer, 2021, 127(16): 3029-3030.
2. Qiu H, Cao S, Xu R. Cancer incidence, mortality, and burden in China: a time-trend analysis and comparison with the United States and United Kingdom based on the global epidemiological data released in 2020. Cancer Commun (Lond), 2021, 41(10): 1037-1048.
3. Zheng RS, Zhang SW, Zeng HM, et al. Cancer incidence and mortality in China, 2016. JNCC, 2022, 2(1): 1-9.
4. Baudino TA. Targeted cancer therapy: the next generation of cancer treatment. Curr Drug Discov Technol, 2015, 12(1): 3-20.
5. Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol, 2018, 834: 188-196.
6. Cao W, Xing H, Li Y, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res, 2022, 10(1): 38.
7. Otani T, Furuse M. Tight junction structure and function revisited. Trends Cell Biol, 2020, 30(10): 805-817.
8. Zihni C, Mills C, Matter K, et al. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol, 2016, 17(9): 564-580.
9. Kyuno D, Takasawa A, Takasawa K, et al. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers, 2022, 10(1): 1967080.
10. Gowrikumar S, Singh AB, Dhawan P. Role of claudin proteins in regulating cancer stem cells and chemoresistance-potential implication in disease prognosis and therapy. Int J Mol Sci, 2019, 21(1): 53.
11. Morin PJ. Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res, 2005, 65(21): 9603-9606.
12. Ouban A. Claudin-1 role in colon cancer: an update and a review. Histol Histopathol, 2018, 33(10): 1013-1019.
13. Niclauss N, Gütgemann I, Dohmen J, et al. Novel biomarkers of gastric adenocarcinoma: current research and future perspectivesv. Cancers (Basel), 2021, 13(22): 5660.
14. Cheung ST, Leung KL, Ip YC, et al. Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma. Clin Cancer Res, 2005, 11(2 Pt 1): 551-556.
15. Luo J, Chimge NO, Zhou B, et al. CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro. Int J Cancer, 2018, 143(12): 3169-3180.
16. Iwaya M, Hayashi H, Nakajima T, et al. Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy. Histopathology, 2021, 79(2): 227-237.
17. Kage H, Flodby P, Zhou B, et al. Dichotomous roles of claudins as tumor promoters or suppressors: lessons from knockout mice. Cell Mol Life Sci, 2019, 76(23): 4663-4672.
18. Shu Y, Zhang W, Hou Q, et al. Prognostic significance of frequent CLDN18-ARHGAP26/6 fusion in gastric signet-ring cell cancer. Nat Commun, 2018, 9(1): 2447.
19. Tanaka A, Ishikawa S, Ushiku T, et al. Frequent CLDN18-ARHGAP fusion in highly metastatic diffuse-type gastric cancer with relatively early onset. Oncotarget, 2018, 9(50): 29336-29350.
20. Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res, 2008, 14(23): 7624-7634.
21. Yamaguchi H, Kojima T, Ito T, et al. Transcriptional control of tight junction proteins via a protein kinase C signal pathway in human telomerase reverse transcriptase-transfected human pancreatic duct epithelial cells. Am J Pathol, 2010, 177(2): 698-712.
22. Ito T, Kojima T, Yamaguchi H, et al. Transcriptional regulation of claudin-18 via specific protein kinase C signaling pathways and modification of DNA methylation in human pancreatic cancer cells. J Cell Biochem, 2011, 112(7): 1761-1772.
23. Fan L, Chong X, Zhao M, et al. Ultrasensitive gastric cancer circulating tumor cellular CLDN18.2 RNA detection based on a molecular beacon. Anal Chem, 2021, 93(2): 665-670.
24. Wang S, Qi C, Ding J, et al. First-in-human CLDN18.2 functional diagnostic pet imaging of digestive system neoplasms enables whole-body target mapping and lesion detection. Eur J Nucl Med Mol Imaging, 2023, 50(9): 2802-2817.
25. Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol, 2020, 18(3): 534-542.
26. Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev, 2017, 8(8): CD004064.
27. Oh DY, Bang YJ. Pertuzumab in gastrointestinal cancer. Expert Opin Biol Ther, 2016, 16(2): 243-253.
28. Kang BW, Baek DW, Kang H, et al. Novel therapeutic approaches for epstein-barr virus associated gastric cancer. Anticancer Res, 2019, 39(8): 4003-4010.
29. Hsu A, Chudasama R, Almhanna K, et al. Targeted therapies for gastroesophageal cancers. Ann Transl Med, 2020, 8(17): 1104.
30. Baek JH, Park DJ, Kim GY, et al. Clinical implications of Claudin18.2 expression in patients with gastric cancer. Anticancer Res, 2019, 39(12): 6973-6979.
31. Niu Q, Liu JM, Luo XX, et al. Future of targeted therapy for gastrointestinal cancer: Claudin 18.2. Oncol Transl Med, 2021, 7(3): 102-107.
32. Rohde C, Yamaguchi R, Mukhina S, et al. Comparison of Claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol, 2019, 49(9): 870-876.
33. Hong JY, An JY, Lee J, et al. Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer. Transl Cancer Res, 2020, 9(5): 3367-3374.
34. Dottermusch M, Krüger S, Behrens HM, et al. Expression of the potential therapeutic target Claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Arch, 2019, 475(5): 563-571.
35. Weng W, Zhang M, Ni S, et al. Decreased expression of Claudin-18. 2 in alpha-fetoprotein-producing gastric cancer compared to conventional gastric cancer. J Gastrointest Oncol, 2022, 13(3): 1035-1045.
36. Ungureanu BS, Lungulescu CV, Pirici D, et al. Clinicopathologic relevance of Claudin 18.2 expression in gastric cancer: a meta-analysis. Front Oncol, 2021, 11: 643872.
37. Moentenich V, Gebauer F, Comut E, et al. Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies. Oncol Lett, 2020, 19(6): 3665-3670.
38. Sahin U, Schuler M, Richly H, et al. A phase Ⅰ dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer. Eur J Cancer, 2018, 100: 17-26.
39. Singh P, Toom S, Huang Y. Anti-Claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. J Hematol Oncol, 2017, 10(1): 105.
40. Sahin U, Al-Batran SE, Hozaeel W, et al. IMAB362 plus zoledronic acid (ZA) and interleukin-2 (IL-2) in patients (pts) with advanced gastroesophageal cancer (GEC): clinical activity and safety data from the PILOT phaseⅠtrial. J Clin Oncol, 2015, 33(Suppl 15): e15079.
41. Türeci O, Sahin U, Schulze-Bergkamen H, et al. A multicentre, phase Ⅱa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann Oncol, 2019, 30(9): 1487-1495.
42. Sahin U, Türeci ?, Manikhas G, et al. FAST: a randomised phase Ⅱ study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced Claudin18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol, 2021, 32(5): 609-619.
43. Teng F, Gu Y, Chai H, et al. Abstract 5183: the preclinical characterization of TST001, a novel humanized anti-Claudin18.2 mAb with enhanced binding affinity and anti-tumor activity. Cancer Res, 2020, 80(Suppl 16): 5183.
44. Jiang H, Shi Z, Wang P, et al. Claudin18.2-specific chimeric antigen receptor engineered T cells for the treatment of gastric cancer. J Natl Cancer Inst, 2019, 111(4): 409-418.
45. Qi C, Gong J, Li J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med, 2022, 28(6): 1189-1198.
46. Zhu G, Foletti D, Liu X, et al. Targeting CLDN18.2 by CD3 bispecific and ADC modalities for the treatments of gastric and pancreatic cancer. Sci Rep, 2019, 9(1): 8420.
47. McGuigan A, Kelly P, Turkington RC, et al. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol, 2018, 24(43): 4846-4861.
48. Cai J, Chen H, Lu M, et al. Advances in the epidemiology of pancreatic cancer: trends, risk factors, screening, and prognosis. Cancer Lett, 2021, 520: 1-11.
49. Ghosn M, Kourie HR, El Rassy E, et al. Where does chemotherapy stands in the treatment of ampullary carcinoma? A review of literature. World J Gastrointest Oncol, 2016, 8(10): 745-750.
50. Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet, 2011, 378(9791): 607-620.
51. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med, 2011, 364(19): 1817-1825.
52. Basturk O, Khayyata S, Klimstra DS, et al. Preferential expression of MUC6 in oncocytic and pancreatobiliary types of intraductal papillary neoplasms highlights a pyloropancreatic pathway, distinct from the intestinal pathway, in pancreatic carcinogenesis. Am J Surg Pathol, 2010, 34(3): 364-370.
53. W?ll S, Schlitter AM, Dhaene K, et al. Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Int J Cancer, 2014, 134(3): 731-739.
54. Türeci ?, Mitnacht-Kraus R, W?ll S, et al. Characterization of zolbetuximab in pancreatic cancer models. Oncoimmunology, 2018, 8(1): e1523096.
55. Zhan Xianbao, Wang Bin, Li Zonghai, et al. PhaseⅠtrial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma. J Clin Oncol, 2019, 37(Suppl 15): 2509.
56. Matsuda M, Sentani K, Noguchi T, et al. Immunohistochemical analysis of colorectal cancer with gastric phenotype: Claudin-18 is associated with poor prognosis. Pathol Int, 2010, 60(10): 673-680.
57. Relli V, Trerotola M, Guerra E, et al. Abandoning the notion of non-small cell lung cancer. Trends Mol Med, 2019, 25(7): 585-594.
58. Micke P, Mattsson JS, Edlund K, et al. Aberrantly activated Claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer. Int J Cancer, 2014, 135(9): 2206-2214.
59. T?kés AM, Szász AM, Juhász E, et al. Expression of tight junction molecules in breast carcinomas analysed by array PCR and immunohistochemistry. Pathol Oncol Res, 2012, 18(3): 593-606.
60. Arnold A, Daum S, von Winterfeld M, et al. Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas. Clin Transl Oncol, 2020, 22(12): 2357-2363.

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