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Ni SJ, Wang X, Yuan L, Dong H, Sun H, Tan C, Cai X, Jiang W, Sheng W, Xu M, Huang D. Claudin18.2 expression in gallbladder cancer correlates with immune activation and a favourable prognosis. J Clin Pathol 2025:jcp-2024-209914. [PMID: 39947883 DOI: 10.1136/jcp-2024-209914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/06/2025] [Indexed: 03/28/2025]
Abstract
AIMS Gallbladder carcinoma (GBC) is frequently diagnosed and treated in advanced stages and has a poor prognosis. Recent studies have identified claudin18.2 (CLDN18.2) as a promising target in digestive system cancer. In this study, we aimed to determine the expression of CLDN18.2 and its correlation with clinicopathological characteristics in patients with GBC. METHODS The expression of CLDN18.2 of 228 patients with GBC was studied via immunohistochemistry. Immunostained samples were evaluated according to the H-score. The samples were divided into low/negative (H-score=0-49) and high/positive (H-score=50-300) expression groups. The correlations between CLDN18.2 and various clinicopathological characteristics, including survival, were assessed. Multiplex immunofluorescence and image acquisition were used to analyse the relationship between CLDN18.2 expression and the immune microenvironment. RESULTS The overall positive CLDN18.2 staining rate was 39.91% (91/228); 137 (60.08%) were given 0 points, 30 (13.15%) were given 1 point, 28 (12.28%) were given 2 points and 33 (14.47%) were given 3 points. Low CLDN18.2 expression was correlated with adverse prognostic factors, including poor differentiation, deep infiltration depth, lymph node metastasis and distant metastasis. High CLDN18.2 expression was associated with better survival. Furthermore, the distribution of immune cell subsets significantly differed between the high and low CLDN18.2 expression groups. CONCLUSIONS The correlations between the expression of CLDN18.2 and clinicopathological characteristics and prognosis suggest that early-stage patients could benefit more from future anti-CLDN18.2 treatment and that CLDN18.2 may function as a pivotal regulatory molecule in patients with GBC. The underlying mechanism may be related to immune activation caused by high CLDN18.2 expression.
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Affiliation(s)
- Shu-Juan Ni
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
| | - Xin Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
| | - Lin Yuan
- the departmeng of pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Hui Dong
- Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, People's Republic of China
| | - Hui Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
| | - Cong Tan
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
| | - Xu Cai
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
| | - Wenhua Jiang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
| | - Dan Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China
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Xu SX, Wang L, Ip P, Randhawa RR, Benatar T, Prosser SL, Lal P, Khan AN, Nitya-Nootan T, Thakor G, MacGregor H, Hayes DL, Vucicevic A, Mathew P, Sengupta S, Helsen CW, Bader AG. Preclinical Development of T Cells Engineered to Express a T-Cell Antigen Coupler Targeting Claudin 18.2-Positive Solid Tumors. Cancer Immunol Res 2025; 13:35-46. [PMID: 39404622 PMCID: PMC11712040 DOI: 10.1158/2326-6066.cir-24-0138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 05/29/2024] [Accepted: 10/01/2024] [Indexed: 01/11/2025]
Abstract
The T-cell antigen coupler (TAC) is a chimeric receptor that facilitates tumor antigen-specific activation of T cells by co-opting the endogenous T-cell receptor complex in the absence of tonic signaling. Previous data demonstrate that the TAC affords T cells with the ability to induce durable and safe antitumor responses in preclinical models of hematologic and solid tumors. In this study, we describe the preclinical pharmacology and safety of an autologous Claudin 18.2 (CLDN18.2)-directed TAC T-cell therapy, TAC01-CLDN18.2, in preparation for a phase I/II clinical study in subjects with CLDN18.2-positive solid tumors. Following a screen of putative TAC constructs, the specificity, activity, and cytotoxicity of TAC T cells expressing the final CLDN18.2-TAC receptor were evaluated in vitro and in vivo using gastric, gastroesophageal, and pancreatic tumor models as well as human cells derived from normal tissues. CLDN18.2-specific activity and cytotoxicity of CLDN18.2-TAC T cells were observed in coculture with various 2D tumor cultures naturally expressing CLDN18.2 as well as tumor spheroids. These effects occurred in models with low antigen levels and were positively associated with increasing CLDN18.2 expression. CLDN18.2-TAC T cells effectively eradicated established tumor xenografts in mice in the absence of observed off-target or on-target/off-tumor effects, elicited durable efficacy in recursive killing and tumor rechallenge experiments, and remained unreactive in coculture with human cells representing vital organs. Thus, the data demonstrate that CLDN18.2-TAC T cells can induce a specific and long-lasting antitumor response in various CLDN18.2-positive solid tumor models without notable TAC-dependent toxicities, supporting the clinical development of TAC01-CLDN18.2.
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MESH Headings
- Humans
- Animals
- Claudins/metabolism
- Claudins/genetics
- Mice
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Neoplasms/therapy
- Neoplasms/immunology
- Xenograft Model Antitumor Assays
- Cell Line, Tumor
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/genetics
- Immunotherapy, Adoptive/methods
- Female
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/metabolism
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Affiliation(s)
- Stacey X. Xu
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Ling Wang
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Philbert Ip
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Ritu R. Randhawa
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Tania Benatar
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Suzanna L. Prosser
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Prabha Lal
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Alima Naim Khan
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Thanyashanthi Nitya-Nootan
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Gargi Thakor
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Heather MacGregor
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Danielle L Hayes
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Andrea Vucicevic
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Princy Mathew
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Sadhak Sengupta
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Christopher W. Helsen
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
| | - Andreas G. Bader
- Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada
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Tojjari A, Idrissi YA, Saeed A. Emerging targets in gastric and pancreatic cancer: Focus on claudin 18.2. Cancer Lett 2024; 611:217362. [PMID: 39637967 DOI: 10.1016/j.canlet.2024.217362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/28/2024] [Accepted: 12/01/2024] [Indexed: 12/07/2024]
Abstract
Recently, the molecular landscape of gastric and pancreatic cancers has advanced with Claudin 18.2 (CLDN18.2) emerging as a promising therapeutic target. Claudin 18.2, a tight junction protein, is selectively expressed in cancer cells and minimally in normal tissues, making it an attractive candidate for targeted therapy. Therapies like monoclonal antibodies (e.g., zolbetuximab), bispecific antibodies, and antibody-drug conjugates have shown significant potential in improving clinical outcomes. Early-phase clinical trials demonstrate robust antitumor activity, particularly in combination with chemotherapy and immunotherapy regimens. However, challenges such as patient selection, resistance mechanisms, and toxicity management remain critical. This review highlights the therapeutic landscape, clinical advancements, and future directions of targeting Claudin 18.2 in gastric and pancreatic cancer treatment.
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Affiliation(s)
- Alireza Tojjari
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15213, USA.
| | - Yassine Alami Idrissi
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15213, USA.
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15213, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
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Kinugasa F, Kajikawa S, Weng J, Ugawa T, Fushiki H, Yamanaka Y, Nagata M, Haggerty G, Akuzawa S, Nakazawa T, Suzuki H, Sawamoto T. Effect of antiemetics on zolbetuximab-induced gastric injury and emesis in ferrets. J Pharmacol Sci 2024; 156:161-170. [PMID: 39313274 DOI: 10.1016/j.jphs.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 07/30/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Claudin-18 splice variant 2 (CLDN18.2), a tight junction protein, is a highly cell type-specific antigen that is expressed by differentiated gastric mucosa cells. The expression of CLDN18.2 in gastric mucosa cells may be retained upon malignant transformation and is displayed on the surface of several tumors, including gastric/gastroesophageal junction adenocarcinoma. Zolbetuximab is a genetically engineered, highly purified chimeric (mouse/human IgG1) antibody directed against CLDN18.2. Nausea and vomiting were observed as adverse events of zolbetuximab. To investigate the mechanism of nausea and vomiting in humans, we evaluated emesis (retching and vomiting) and conducted histopathologic assessment in ferrets after the administration of zolbetuximab. Emesis was frequently observed in all ferrets treated with zolbetuximab in the first hour after administration. Histopathologic assessment revealed the surface of the gastric mucosa was the primary site of emesis-associated tissue damage. The effect of antiemetics (dexamethasone, ondansetron, fosaprepitant, and olanzapine) on emesis induced by zolbetuximab was investigated. Fosaprepitant showed suppressive effects on emesis, and use of dexamethasone or concomitant use of fosaprepitant with other antiemetics tended to alleviate gastric tissue damage. The onset of emesis in humans receiving zolbetuximab may be associated with damage in the gastric mucosa, and antiemetics may mitigate gastrointestinal adverse events.
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Affiliation(s)
- Fumitaka Kinugasa
- Research Program Management - Applied Research Management, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan.
| | - Satoru Kajikawa
- Applied Safety - Non-clinical Regulatory Science, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
| | - Jane Weng
- Research Program Management - Applied Research Management, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
| | - Tohru Ugawa
- Regulatory Management - Non-clinical Regulatory Science, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
| | - Hiroshi Fushiki
- Research Program Management - Applied Research Management, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
| | - Yosuke Yamanaka
- Applied Drug Metabolism & Pharmacokinetics - Non-clinical Regulatory Science, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
| | - Masanori Nagata
- Biomarker Discovery & Development - Non-clinical Biomedical Science, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
| | - Gillian Haggerty
- Translational Science & Development Toxicology - Applied Safety, Astellas Pharma US, Inc., Northbrook, IL, USA
| | - Shinobu Akuzawa
- Applied Pharmacology - Non-clinical Regulatory Science, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
| | | | - Hiroshi Suzuki
- Applied Research Management, Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
| | - Taiji Sawamoto
- Applied Research & Operations, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan
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Fassan M, Kuwata T, Matkowskyj KA, Röcken C, Rüschoff J. Claudin-18.2 Immunohistochemical Evaluation in Gastric and Gastroesophageal Junction Adenocarcinomas to Direct Targeted Therapy: A Practical Approach. Mod Pathol 2024; 37:100589. [PMID: 39098518 DOI: 10.1016/j.modpat.2024.100589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/14/2024] [Accepted: 07/29/2024] [Indexed: 08/06/2024]
Abstract
Claudin-18.2 (CLDN18.2) expression evaluated by immunohistochemistry is a new biomarker for gastric and gastroesophageal junction adenocarcinomas that will soon have market authorization for implementation into routine clinical practice. Despite successful testing in the setting of clinical trials, no specific practical testing guidelines have been proposed. Several preanalytical and analytical variables may interfere with adequate CLDN18.2 staining interpretation; thus, this article provides practical guidance on CLDN18.2 testing and scoring in gastric and gastroesophageal junction adenocarcinomas to identify patients who may respond to targeted therapy with monoclonal antibodies directed against CLDN18.2. Based on available data, moderate to strong (2+/3+) membrane staining in ≥75% of adenocarcinoma cells is the proposed cutoff for clinical use of monoclonal antibody anti-CLDN18.2 (zolbetuximab).
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Affiliation(s)
- Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy; Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.
| | - Takeshi Kuwata
- Department of Genetic Medicine and Services, National Cancer Center Hospital East, Chiba, Japan
| | | | - Christoph Röcken
- Department of Pathology, University-Hospital Schleswig-Holstein (UKSH), Kiel, Germany
| | - Josef Rüschoff
- Discovery Life Sciences Biomarker Services, Kassel, Germany
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Wu J, Lu J, Chen Q, Chen H, Zheng Y, Cheng M. Pan-cancer analysis of CLDN18.2 shed new insights on the targeted therapy of upper gastrointestinal tract cancers. Front Pharmacol 2024; 15:1494131. [PMID: 39555091 PMCID: PMC11563798 DOI: 10.3389/fphar.2024.1494131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 10/14/2024] [Indexed: 11/19/2024] Open
Abstract
Background CLDN18.2 is a widely researched drug target. However, previous research has primarily been based on immunohistochemistry results and focused on gastric cancer. Methods To analyze the potential cancer-targeting effect of CLDN18.2 from a multi-omics perspective, this study quantified CLDN18.2 expression in The Cancer Genome Atlas (TCGA) pan-cancer cohort. Thus, the relationships between CLDN18.2 expression and genomic alterations, immune infiltration, and prognosis were analyzed. Additionally, we performed analyses of the differentially expressed genes and enriched pathways between the high- and low-CLDN18.2 expression groups, as well as the corresponding drug sensitivity analyses. Results The results indicated that CLDN18.2 was highly expressed in pancreatic adenocarcinoma (PAAD), stomach adenocarcinoma (STAD), colorectal cancer (CRC), and esophageal carcinoma (ESCA). Moreover, the high- and low-CLDN18.2 expression groups presented significant differences in terms of genomic alterations and immune infiltration, such as the levels of methylation and CD4+ T cell infiltration. Furthermore, high CLDN18.2 expression was significantly associated with poor prognosis in bladder urothelial carcinoma (BLCA), ESCA, and PAAD. In upper gastrointestinal tract cancers (STAD, ESCA, and PAAD), downregulated gene-enriched pathways were associated with cell signaling, whereas upregulated gene-enriched pathways were associated with angiogenesis. Finally, we identified drugs associated with CLDN18.2 expression to which samples with different levels of expression were differentially sensitive. Conclusion CLDN18.2 was highly expressed in upper gastrointestinal tract cancers, and its expression had a significant effect on genomic alterations and the tumor microenvironment. Additionally, low CLDN18.2 expression was linked to favorable prognosis. Our study reveals the potential value of CLDN18.2 for tumor prognosis and targeted therapy in various cancers, especially upper gastrointestinal tract cancers.
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Affiliation(s)
- Jun Wu
- Department of Clinical Laboratory, People's Hospital of Bao'an District, Shenzhen Baoan Clinical Medical College of Guangdong Medical University, Shenzhen, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jinghua Lu
- Department of Clinical Laboratory, People's Hospital of Bao'an District, Shenzhen Baoan Clinical Medical College of Guangdong Medical University, Shenzhen, China
| | - Qiuyue Chen
- Department of Clinical Laboratory, People's Hospital of Bao'an District, Shenzhen Baoan Clinical Medical College of Guangdong Medical University, Shenzhen, China
| | - Haojie Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yongqiang Zheng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Minggang Cheng
- Department of Clinical Laboratory, People's Hospital of Bao'an District, Shenzhen Baoan Clinical Medical College of Guangdong Medical University, Shenzhen, China
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Kim M, Kang BW, Park J, Baek JH, Kim JG. Expression of claudin 18.2 in poorly cohesive carcinoma and its association with clinicopathologic parameters in East Asian patients. Pathol Res Pract 2024; 263:155628. [PMID: 39368365 DOI: 10.1016/j.prp.2024.155628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 09/21/2024] [Accepted: 09/27/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Poorly cohesive carcinoma (PCC) is a distinct subtype of gastric cancer with limited therapeutic options. This study investigated claudin (CLDN) 18.2 expression status in PCCs using a 43-13 A clone. METHODS We retrospectively collected 178 consecutive surgically resected stage Ⅱ-Ⅲ gastric cancer samples. Tissue microarray blocks were constructed for CLDN18.2 immunohistochemical staining. We studied CLDN18.2 expression and its association with clinicopathologic parameters. RESULTS CLDN18.2 positivity (defined by ≥ 75 % of tumor cells showing moderate to strong membranous positivity) was found in 34.8 % of the PCC cases (62/178). Approximately half of the CLDN18.2 positive PCCs demonstrated heterogeneous expression (51.6 %, 32/62). CLDN18.2 positivity was not associated with any clinicopathologic parameters examined. However, CLDN18.2 positivity tended to be more frequent in E-cadherin-positive PCCs (no loss of expression) than in E-cadherin-negative PCCs (loss of expression) (50 % vs. 27.7 %). The CLDN18.2 expression level, represented by the H-score, gradually decreased as the paraffin block storage time increased (P = 0.046). Overall survival and disease-free survival analyses showed no significant difference between CLDN18.2-positive and negative PCCs. CONCLUSIONS A significant portion of surgically resected PCC specimens showed CLDN18.2 positivity. Additionally, since the expression level of CLDN18.2 gradually decreases with increased paraffin block storage time, reflex testing can be considered at the time of the cancer diagnosis.
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Affiliation(s)
- Moonsik Kim
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Byung Woog Kang
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Kyungpook National University Cancer Research Institute, Daegu, Republic of Korea
| | - Jihyun Park
- Department of Pathology, Yonsei University College of Medicine, Republic of Korea
| | - Jin Ho Baek
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Kyungpook National University Cancer Research Institute, Daegu, Republic of Korea
| | - Jong Gwang Kim
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Kyungpook National University Cancer Research Institute, Daegu, Republic of Korea.
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Jeon H, Sterpi M, Mo C, Bteich F. Claudins: from gatekeepers of epithelial integrity to potential targets in hepato-pancreato-biliary cancers. Front Oncol 2024; 14:1454882. [PMID: 39391254 PMCID: PMC11464258 DOI: 10.3389/fonc.2024.1454882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 08/22/2024] [Indexed: 10/12/2024] Open
Abstract
Claudins, a family of tetraspan transmembrane proteins, are critical to the integrity of tight junctions in epithelia and endothelia, influencing cellular processes such as development, differentiation, and apoptosis. Abnormal claudin expression is associated with various malignancies, particularly affecting tissue architecture and potentially facilitating tumor invasion and metastasis. In this comprehensive review, we explore the multifaceted functions of claudins: their expression, specific roles in cancer with a focus on hepato-pancreato-biliary malignancies and highlight their potential as therapeutic targets. We discuss current claudin-targeted therapies, including monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engager and chimeric antigen receptor T-cell therapies. These approaches show promise in pre-clinical and clinical studies, particularly in hepato-pancreato-biliary cancers with large unmet needs. Despite these early signs of efficacy, challenges remain in effectively targeting these proteins due to their structural resemblance and overlapping functions.
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Affiliation(s)
- Hyein Jeon
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States
| | - Michelle Sterpi
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States
| | - Christiana Mo
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States
| | - Fernand Bteich
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, United States
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Zeng Y, Lockhart AC, Jin RU. The preclinical discovery and development of zolbetuximab for the treatment of gastric cancer. Expert Opin Drug Discov 2024; 19:873-886. [PMID: 38919123 PMCID: PMC11938084 DOI: 10.1080/17460441.2024.2370332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 06/04/2024] [Accepted: 06/17/2024] [Indexed: 06/27/2024]
Abstract
INTRODUCTION Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy. AREAS COVERED The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer. EXPERT OPINION CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.
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Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - A. Craig Lockhart
- Division of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ramon U. Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA
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Meng Q, Hao Y, Yang M, Du Y, Wang S. Development and validation of ELISA method for quantification of Q-1802 in serum and its application to pharmacokinetic study in ICR Mouse. J Pharm Biomed Anal 2024; 245:116138. [PMID: 38636191 DOI: 10.1016/j.jpba.2024.116138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 03/11/2024] [Accepted: 04/05/2024] [Indexed: 04/20/2024]
Abstract
Q-1802 is a humanized bispecific antibody targeting programmed death-ligand 1 (PD-L1) and Claudin 18.2 (CLDN18.2). It can bind to CLDN18.2 and mediate antibody-dependent cell-mediated cytotoxicity against tumor cells. The Fc segment of the antibody recognizing PD-L1 blocks PD-1 signaling and activates innate immunity and adaptive immunity. In this study, we report the development, validation, and application of sensitive and high-throughput enzyme-linked immunosorbent assays (ELISA) to measure the concentrations of Q-1802 in ICR mouse serum. The assay is sensitive, with a lower limit of quantification of 50 ng/mL, has a broad dynamic range of 50-3200 ng/mL, and exhibits excellent precision and accuracy. These assays were successfully applied to in vitro serum stability and pharmacokinetic (PK) studies. In conclusion, we have developed and validated a highly sensitive and selective method for measuring Q-1802 in ICR mouse serum. The development and validation steps of assays met the required criteria for validation, which suggested that these can be applied to quantify Q-1802, as well as in PK studies.
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Affiliation(s)
- Qinghe Meng
- Shenyang Pharmaceutical University, Shenyang, China
| | - Yimeng Hao
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Mo Yang
- Medicilon Preclinical Research (Shanghai) LLC, Shanghai, China
| | - Yejie Du
- Qure Biotechnology (Shanghai) Co., Ltd, Shanghai, China
| | - Shuling Wang
- Shenyang Pharmaceutical University, Shenyang, China.
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11
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Wu J, Chen J, Zhao Y, Yuan M, Chen X, He X, Zhang J, Shao G, Sun Q. Molecular SPECT/CT Profiling of Claudin18.2 Expression In Vivo: Implication for Patients with Gastric Cancer. Mol Pharm 2024; 21:3447-3458. [PMID: 38843446 DOI: 10.1021/acs.molpharmaceut.4c00155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Zolbetuximab (IMAB362), a monoclonal antibody targeting Claudin18.2 (CLDN 18.2), demonstrates a significant clinical benefit in patients with advanced gastroesophageal cancers. The noninvasive assessment of CLDN18.2 expression through molecular imaging offers a potential avenue for expedited monitoring and the stratification of patients into risk groups. This study elucidates that CLDN18.2 is expressed at a noteworthy frequency in primary gastric cancers and their metastases. The iodogen method was employed to label IMAB362 with 123I/131I. The results demonstrated the efficient and reproducible synthesis of 123I-IMAB362, with a specific binding affinity to CLDN18.2. Immuno-single-photon emission computed tomography (SPECT) imaging revealed the rapid accumulation of 123I-IMAB362 in gastric cancer xenografts at 12 h, remaining stable for 3 days in patient-derived tumor xenograft models. Additionally, tracer uptake of 123I-IMAB362 in MKN45 cells surpassed that in MKN28 cells at each time point, with tumor uptake correlating significantly with CLDN18.2 expression levels. Positron emission tomography/computed tomography imaging indicated that tumor uptake of 18F-FDG and the functional/viable tumor volume in the 131I-IMAB362 group were significantly lower than those in the 123I-IMAB362 group on day 7. In conclusion, 123I-IMAB362 immuno-SPECT imaging offers an effective method for direct, noninvasive, and whole-body quantitative assessment of tumor CLDN18.2 expression in vivo. This approach holds promise for accelerating the monitoring and stratification of patients with gastric cancer.
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Affiliation(s)
- Jian Wu
- Department of Science and Technology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Jun Chen
- Department of Nuclear Medicine, The Affiliated Taizhou People's Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, China
- Department of Nuclear Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Yuetong Zhao
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Mengyun Yuan
- Department of Science and Technology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Xu Chen
- Department of Science and Technology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Xiangdong He
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Jun Zhang
- Department of Nuclear Medicine, The Affiliated Taizhou People's Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, China
- Department of Nuclear Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Guoqiang Shao
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Qingmin Sun
- Department of Science and Technology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
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12
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Jin WM, Zhu Y, Cai ZQ, He N, Yu ZQ, Li S, Yang JY. Progress of Clinical Studies Targeting Claudin18.2 for the Treatment of Gastric Cancer. Dig Dis Sci 2024; 69:2631-2647. [PMID: 38769225 DOI: 10.1007/s10620-024-08435-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 04/10/2024] [Indexed: 05/22/2024]
Abstract
Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value.
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Affiliation(s)
- Wu-Mei Jin
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Yan Zhu
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Zhi-Qiang Cai
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Na He
- Department of General, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Zhi-Qiong Yu
- Department of Respiratory, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Shuang Li
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Ji-Yuan Yang
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China.
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13
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Katoh M, Nakayama I, Wainberg ZA, Shitara K, Katoh M. Monoclonal antibodies that target fibroblast growth factor receptor 2 isoform b and Claudin-18 isoform 2 splicing variants in gastric cancer and other solid tumours. Clin Transl Med 2024; 14:e1736. [PMID: 38877656 PMCID: PMC11178514 DOI: 10.1002/ctm2.1736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/16/2024] Open
Affiliation(s)
| | - Izuma Nakayama
- Department of Gastroenterology and Gastrointestinal OncologyNational Cancer Center Hospital EastKashiwaJapan
| | - Zev A Wainberg
- Department of MedicineUniversity of California Los AngelesLos AngelesCaliforniaUSA
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal OncologyNational Cancer Center Hospital EastKashiwaJapan
| | - Masaru Katoh
- M & M Precision MedicineTokyoJapan
- Department of Omics NetworkNational Cancer CenterTokyoJapan
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14
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Kuwata T. Molecular classification and intratumoral heterogeneity of gastric adenocarcinoma. Pathol Int 2024; 74:301-316. [PMID: 38651937 PMCID: PMC11551831 DOI: 10.1111/pin.13427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/25/2024] [Accepted: 04/03/2024] [Indexed: 04/25/2024]
Abstract
Gastric cancers frequently harbor striking histological complexity and diversity between lesions as well as within single lesions, known as inter- and intratumoral heterogeneity, respectively. The latest World Health Organization Classification of Tumors designated more than 30 histological subtypes for gastric epithelial tumors, assigning 12 subtypes for gastric adenocarcinoma (GAD). Meanwhile, recent advances in genome-wide analyses have provided molecular aspects to the histological classification of GAD, and consequently revealed different molecular traits underlying these histological subtypes. Moreover, accumulating knowledge of comprehensive molecular profiles has led to establishing molecular classifications of GAD, which are often associated with clinical biomarkers for therapeutics and prognosis. However, most of our knowledge of GAD molecular profiles is based on inter-tumoral heterogeneity, and the molecular profiles underlying intratumoral heterogeneity are yet to be determined. In this review, recently established molecular classifications of GAD are introduced in the aspect of pathological diagnosis and are discussed in the context of intratumoral heterogeneity.
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Affiliation(s)
- Takeshi Kuwata
- Department of Genetic Medicine and ServicesNational Cancer Center Hospital EastKashiwaChibaJapan
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15
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Nakayama I, Qi C, Chen Y, Nakamura Y, Shen L, Shitara K. Claudin 18.2 as a novel therapeutic target. Nat Rev Clin Oncol 2024; 21:354-369. [PMID: 38503878 DOI: 10.1038/s41571-024-00874-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2024] [Indexed: 03/21/2024]
Abstract
Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody-drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.
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Affiliation(s)
- Izuma Nakayama
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Changsong Qi
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yang Chen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- International Research Promotion Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Lin Shen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
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16
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Wang J, Dong T, Gong X, Li D, Sun J, Luo Y, Wu H. Safety and Pharmacokinetic Assessment of the FIC CLDN18.2/4-1BB Bispecific Antibody in Rhesus Monkeys. Int J Toxicol 2024; 43:291-300. [PMID: 38115178 DOI: 10.1177/10915818231221282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
Gastric cancer is one of the most common cancers worldwide, particularly in China, with over half a million new cases and over 400 thousand deaths in 2022. Zolbetuximab, a first-in-class investigational monoclonal antibody (mAb) targeting tumor-associated antigen CLDN18.2 which is highly expressed on gastric cancer cells, was recently reported to meet the primary endpoint in Phase III trial as first-line treatment in CLDN18.2 positive and HER2-negative gastric cancers. In the present study, we developed a humanized bispecific antibody (bsAb) CLDN18.2/4-1BB named PM1032. PM1032 activates immune cells via CLDN18.2 mediated crosslinking of 4-1BB, a potent stimulator of T/NK cells. It induced strong immunological memory in multiple tumor-bearing animal models, indicating significant potential as an effective treatment for CLDN18.2 positive cancers such as gastric cancer. Since liver and gastrointestinal (GI) related toxicities were reported in 4-1BB and CLDN18.2 targeting programs during the clinical development, respectively, extensive pharmacokinetics (PK) and safety profile characterization of PM1032 was performed in rhesus monkeys. PM1032 had a half-life comparable to a conventional IgG1 mAb, and serum drug concentration increased in a dose-dependent pattern. Furthermore, PM1032 was generally well tolerated, with no significant abnormalities observed in toxicity studies, including the liver and stomach. In summary, PM1032 demonstrated good PK and an exceptional safety profile in rhesus monkeys supporting further investigation in clinical studies.
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Affiliation(s)
- Jing Wang
- School of Life Sciences, Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
- TriApex Laboratories Co., Ltd, Nanjing, China
| | - Tiantian Dong
- New Drug Technology Department, Biotheus Inc., Zhuhai, China
- TriApex Laboratories Co., Ltd, Nanjing, China
| | - Xinjiang Gong
- New Drug Technology Department, Biotheus Inc., Zhuhai, China
- TriApex Laboratories Co., Ltd, Nanjing, China
| | - Deli Li
- TriApex Laboratories Co., Ltd, Nanjing, China
| | - Joanne Sun
- New Drug Technology Department, Biotheus Inc., Zhuhai, China
| | - Yi Luo
- New Drug Discovery and Development, Biotheus Inc., Zhuhai, China
- Clinical Pharmacy Innovation Institute, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Huazhang Wu
- School of Life Sciences, Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
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17
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Zeng Z, Li L, Tao J, Liu J, Li H, Qian X, Yang Z, Zhu H. [ 177Lu]Lu-labeled anti-claudin-18.2 antibody demonstrated radioimmunotherapy potential in gastric cancer mouse xenograft models. Eur J Nucl Med Mol Imaging 2024; 51:1221-1232. [PMID: 38062170 DOI: 10.1007/s00259-023-06561-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 12/01/2023] [Indexed: 03/22/2024]
Abstract
PURPOSE Gastric cancer (GC), one of the most prevalent and deadliest tumors worldwide, is often diagnosed at an advanced stage with limited treatment options and poor prognosis. The development of a CLDN18.2-targeted radioimmunotherapy probe is a potential treatment option for GC. METHODS The CLDN18.2 antibody TST001 (provided by Transcenta) was conjugated with DOTA and radiolabeled with the radioactive nuclide 177Lu. The specificity and targeting ability were evaluated by cell uptake, imaging and biodistribution experiments. In BGC823CLDN18.2/AGSCLDN18.2 mouse models, the efficacy of [177Lu]Lu-TST001 against CLDN18.2-expressing tumors was demonstrated, and toxicity was evaluated by H&E staining and blood sample testing. RESULTS [177Lu]Lu-TST001 was labeled with an 99.17%±0.32 radiochemical purity, an 18.50 ± 1.27 MBq/nmol specific activity and a stability of ≥ 94% after 7 days. It exhibited specific and high tumor uptake in CLDN18.2-positive xenografts of GC mouse models. Survival studies in BGC823CLDN18.2 and AGSCLDN18.2 tumor-bearing mouse models indicated that a low dose of 5.55 MBq and a high dose of 11.10 MBq [177Lu]Lu-TST001 significantly inhibited tumor growth compared to the saline control group, with the 11.1 MBq group showing better therapeutic efficacy. Histological staining with hematoxylin and eosin (H&E) and Ki67 immunohistochemistry of residual tissues confirmed tumor tissue destruction and reduced tumor cell proliferation following treatment. H&E showed that there was no significant short-term toxicity observed in the heart, spleen, stomach or other important organs when treated with a high dose of [177Lu]Lu-TST001, and no apparent hematotoxicity or liver toxicity was observed. CONCLUSION In preclinical studies, [177Lu]Lu-TST001 demonstrated significant antitumor efficacy with acceptable toxicity. It exhibits strong potential for clinical translation, providing a new promising treatment option for CLDN18.2-overexpressing tumors, including GC.
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Affiliation(s)
- Ziqing Zeng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Liqiang Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jinping Tao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jiayue Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Hongjun Li
- Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, China
| | - Xueming Qian
- Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, China
| | - Zhi Yang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Hua Zhu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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18
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Xu Q, Jia C, Ou Y, Zeng C, Jia Y. Dark horse target Claudin18.2 opens new battlefield for pancreatic cancer. Front Oncol 2024; 14:1371421. [PMID: 38511141 PMCID: PMC10951399 DOI: 10.3389/fonc.2024.1371421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 02/23/2024] [Indexed: 03/22/2024] Open
Abstract
Pancreatic cancer is one of the deadliest malignant tumors, which is a serious threat to human health and life, and it is expected that pancreatic cancer may be the second leading cause of cancer death in developed countries by 2030. Claudin18.2 is a tight junction protein expressed in normal gastric mucosal tissues, which is involved in the formation of tight junctions between cells and affects the permeability of paracellular cells. Claudin18.2 is highly expressed in pancreatic cancer and is associated with the initiation, progression, metastasis and prognosis of cancer, so it is considered a potential therapeutic target. Up to now, a number of clinical trials for Claudin18.2 are underway, including solid tumors such as pancreatic cancers and gastric cancers, and the results of these trials have not yet been officially announced. This manuscript briefly describes the Claudia protein, the dual roles of Cluadin18 in cancers, and summarizes the ongoing clinical trials targeting Claudin18.2 with a view to integrating the research progress of Claudin18.2 targeted therapy. In addition, this manuscript introduces the clinical research progress of Claudin18.2 positive pancreatic cancer, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, CAR-T cell therapy, and hope to provide feasible ideas for the clinical treatment of Claudin18.2 positive pancreatic cancer.
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Affiliation(s)
- Qian Xu
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Caiyan Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yan Ou
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chuanxiu Zeng
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yingjie Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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19
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Stan A, Bosart K, Kaur M, Vo M, Escorcia W, Yoder RJ, Bouley RA, Petreaca RC. Detection of driver mutations and genomic signatures in endometrial cancers using artificial intelligence algorithms. PLoS One 2024; 19:e0299114. [PMID: 38408048 PMCID: PMC10896512 DOI: 10.1371/journal.pone.0299114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/05/2024] [Indexed: 02/28/2024] Open
Abstract
Analyzed endometrial cancer (EC) genomes have allowed for the identification of molecular signatures, which enable the classification, and sometimes prognostication, of these cancers. Artificial intelligence algorithms have facilitated the partitioning of mutations into driver and passenger based on a variety of parameters, including gene function and frequency of mutation. Here, we undertook an evaluation of EC cancer genomes deposited on the Catalogue of Somatic Mutations in Cancers (COSMIC), with the goal to classify all mutations as either driver or passenger. Our analysis showed that approximately 2.5% of all mutations are driver and cause cellular transformation and immortalization. We also characterized nucleotide level mutation signatures, gross chromosomal re-arrangements, and gene expression profiles. We observed that endometrial cancers show distinct nucleotide substitution and chromosomal re-arrangement signatures compared to other cancers. We also identified high expression levels of the CLDN18 claudin gene, which is involved in growth, survival, metastasis and proliferation. We then used in silico protein structure analysis to examine the effect of certain previously uncharacterized driver mutations on protein structure. We found that certain mutations in CTNNB1 and TP53 increase protein stability, which may contribute to cellular transformation. While our analysis retrieved previously classified mutations and genomic alterations, which is to be expected, this study also identified new signatures. Additionally, we show that artificial intelligence algorithms can be effectively leveraged to accurately predict key drivers of cancer. This analysis will expand our understanding of ECs and improve the molecular toolbox for classification, diagnosis, or potential treatment of these cancers.
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Affiliation(s)
- Anda Stan
- Biology Program, The Ohio State University, Marion, Ohio, United States of America
| | - Korey Bosart
- Biology Program, The Ohio State University, Marion, Ohio, United States of America
| | - Mehak Kaur
- Biology Program, The Ohio State University, Marion, Ohio, United States of America
| | - Martin Vo
- Biology Department, Xavier University, Cincinnati, Ohio, United States of America
| | - Wilber Escorcia
- Biology Department, Xavier University, Cincinnati, Ohio, United States of America
| | - Ryan J Yoder
- Department of Chemistry and Biochemistry, The Ohio State University, Marion, Ohio, United States of America
| | - Renee A Bouley
- Department of Chemistry and Biochemistry, The Ohio State University, Marion, Ohio, United States of America
| | - Ruben C Petreaca
- Department of Molecular Genetics, The Ohio State University, Marion, Ohio, United States of America
- James Comprehensive Cancer Center, The Ohio State University Columbus, Columbus, Ohio, United States of America
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20
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Li D, Ding L, Chen Y, Wang Z, Zeng Z, Ma X, Huang H, Li H, Qian X, Yang Z, Zhu H. Exploration of radionuclide labeling of a novel scFv-Fc fusion protein targeting CLDN18.2 for tumor diagnosis and treatment. Eur J Med Chem 2024; 266:116134. [PMID: 38266552 DOI: 10.1016/j.ejmech.2024.116134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/04/2024] [Accepted: 01/07/2024] [Indexed: 01/26/2024]
Abstract
PURPOSE Claudin 18.2 (CLDN18.2), due to its highly selective expression in tumor cells, has made breakthrough progress in clinical research and is expected to be integrated into routine tumor diagnosis and treatment. METHODS In this research, we obtained an scFv-Fc fusion protein (SF106) targeting CLDN18.2 through hybridoma technology. The scFv-Fc fusion protein was labeled with radioactive isotopes (124I and 177Lu) to generate the radio-probes. The targeting and specificity of the radio-probes were tested in cellular models, and its diagnostic and therapeutic potential was further evaluated in tumor-bearing models. RESULTS The molecular probes [124I]I-SF106 and [177Lu]Lu-DOTA-SF106 possess high radiochemical purity (RCP, 98.18 ± 0.93 % and 97.05 ± 1.1 %) and exhibit good stability in phosphate buffer saline and 5 % human serum albumin (92.44 ± 4.68 % and 91.03 ± 2.42 % at 120 h). [124I]I-SF106 uptake in cells expressing CLDN18.2 was well targeted and specific, and the dissociation constant was 17.74 nM [124I]I-SF106 micro-PET imaging showed that the maximum standardized uptake value (SUVmax) was significantly higher than CLDN18.2-negative tumors (1.83 ± 0.02 vs. 1.23 ± 0.04, p < 0.001). The maximum uptake was attained in tumors expressing CLDN18.2 at 48 h after injection. [124I]I-SF106 and [177Lu]Lu-DOTA-SF106 dosimetric study showed that the effective dose in humans complies with the medical safety standards required for their clinical application. The results of treatment experiments showed that 3 MBq of [177Lu]Lu-DOTA-SF106 in CLDN18.2-expressing tumor-bearing mice could significantly inhibit tumor growth. CONCLUSION These results indicate that radionuclide-labeled scFv-Fc molecular probes ([124I]I-SF106 and [177Lu]Lu-DOTA-SF106) provide a new possibility for the diagnosis and treatment of CLDN18.2-positive cancer patients in clinical practice.
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Affiliation(s)
- Dapeng Li
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Lei Ding
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Anesthesiology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yan Chen
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zilei Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Ziqing Zeng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xiaopan Ma
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Haifeng Huang
- Department of Orthopedics, Guizhou Provincial People's Hospital, Guiyang, 550025, Guizhou, China
| | - Hongjun Li
- Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, 215000, China
| | - Xueming Qian
- Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, 215000, China.
| | - Zhi Yang
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Hua Zhu
- Medical College, Guizhou University, Guiyang, 550025, Guizhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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21
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Mathias-Machado MC, de Jesus VHF, Jácome A, Donadio MD, Aruquipa MPS, Fogacci J, Cunha RG, da Silva LM, Peixoto RD. Claudin 18.2 as a New Biomarker in Gastric Cancer-What Should We Know? Cancers (Basel) 2024; 16:679. [PMID: 38339430 PMCID: PMC10854563 DOI: 10.3390/cancers16030679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric cancer (GC) remains a formidable global health challenge, ranking among the top-five causes of cancer-related deaths worldwide. The majority of patients face advanced stages at diagnosis, with a mere 6% five-year survival rate. First-line treatment for metastatic GC typically involves a fluoropyrimidine and platinum agent combination; yet, predictive molecular markers have proven elusive. This review navigates the evolving landscape of GC biomarkers, with a specific focus on Claudin 18.2 (CLDN18.2) as an emerging and promising target. Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. As this novel therapeutic avenue unfolds, understanding the nuanced decision making regarding the selection of anti-CLDN18.2 therapies over other targeted agents in metastatic GC becomes crucial. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC.
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Affiliation(s)
- Maria Cecília Mathias-Machado
- Division of Gastrointestinal Medical Oncology, Oncoclínicas, São Paulo 04538-132, Brazil; (M.D.D.); (M.P.S.A.); (R.D.P.)
| | | | - Alexandre Jácome
- Division of Gastrointestinal Medical Oncology, Oncoclínicas, Belo Horizonte 30360-680, Brazil;
| | - Mauro Daniel Donadio
- Division of Gastrointestinal Medical Oncology, Oncoclínicas, São Paulo 04538-132, Brazil; (M.D.D.); (M.P.S.A.); (R.D.P.)
| | | | - João Fogacci
- Division of Gastrointestinal Medical Oncology, Oncoclínicas, Rio de Janeiro 22775-003, Brazil;
| | - Renato Guerino Cunha
- Cellular Therapy Program, Division of Hematology, Oncoclínicas, São Paulo 04538-132, Brazil;
| | | | - Renata D’Alpino Peixoto
- Division of Gastrointestinal Medical Oncology, Oncoclínicas, São Paulo 04538-132, Brazil; (M.D.D.); (M.P.S.A.); (R.D.P.)
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22
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Angerilli V, Ghelardi F, Nappo F, Grillo F, Parente P, Lonardi S, Luchini C, Pietrantonio F, Ugolini C, Vanoli A, Fassan M. Claudin-18.2 testing and its impact in the therapeutic management of patients with gastric and gastroesophageal adenocarcinomas: A literature review with expert opinion. Pathol Res Pract 2024; 254:155145. [PMID: 38277741 DOI: 10.1016/j.prp.2024.155145] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 01/10/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Claudin-18.2 (CLDN18.2) is a member of the tight junction protein family and is a highly selective biomarker with frequent abnormal expression during the occurrence and development of various primary malignant tumors, including gastric cancer (GC) and esophago-gastric junction adenocarcinomas (EGJA). For these reasons, CLDN18.2 has been investigated as a therapeutic target for GC/EGJA malignancies. Recently, zolbetuximab has been proposed as a new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced and metastatic GC/EGJA. The use of CLDN18 IHC assays to select patients who might benefit from anti-CLDN18.2 therapy is currently entering clinical practice. In this setting, pathologists play a central role in therapeutic decision-making. Accurate biomarker assessment is essential to ensure the best therapeutic option for patients. In the present review, we provide a comprehensive overview of available evidence on CLDN18.2 testing and its impact on the therapeutic management of patients with GC/EGJA, as well as some practical suggestions for CLDN18.2 staining interpretation and potential pitfalls in the real-world setting.
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Affiliation(s)
- Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Filippo Ghelardi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Floriana Nappo
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy.
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
| | - Sara Lonardi
- Medical Oncology 3, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Clara Ugolini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy; Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy
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23
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Bunga OD, Danilova NV. [Claudin-18.2 and gastric cancer: from physiology to carcinogenesis]. Arkh Patol 2024; 86:92-99. [PMID: 39686903 DOI: 10.17116/patol20248606192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
Today a global problem for humanity is represented by cancer, in particular gastric cancer, which is characterized by high mortality and aggressive course. In this regard, there is a search for new approaches to the diagnosis and therapy of gastric cancer, one of these areas is the study of the expression level of the intercellular adhesion molecule claudin-18.2 in tumor tissue and its use as a target molecule. In the case of various pathological processes, including tumors, the expression profile of claudin-18.2 changes, which indicates its possible role in the initiation and progression of cancer. The aim of this review is to systematize the data on claudin-18.2, its role in normal cell physiology and embryology, as well as in the development of pathological processes in the stomach, its relation to the clinical and morphological characteristics of gastric cancer and importance in biological therapy.
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Affiliation(s)
- O D Bunga
- Lomonosov Moscow State University, Moscow, Russia
| | - N V Danilova
- Lomonosov Moscow State University, Moscow, Russia
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24
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O'Brien NA, McDermott MSJ, Zhang J, Gong KW, Lu M, Hoffstrom B, Luo T, Ayala R, Chau K, Liang M, Madrid AM, Donahue TR, Glaspy JA, Presta L, Slamon DJ. Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody-Drug Conjugate for Treatment of CLDN18.2-Positive Cancers. Mol Cancer Ther 2023; 22:1365-1375. [PMID: 37788341 DOI: 10.1158/1535-7163.mct-23-0353] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/02/2023] [Accepted: 09/29/2023] [Indexed: 10/05/2023]
Abstract
Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with it's absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic mAb and antibody-drug conjugate (ADC) targeting CLDN18.2. A humanized CLDN18.2 specific mAb, CLDN18.2-307-mAb, was generated through immunization in mice followed by full humanization of the mouse mAb sequences. Antibody clones were screened by flow cytometry for selective binding to membrane bound CLDN18.2. A CLDN18.2-directed ADC (CLDN18.2-307-ADC) was also generated by conjugating MMAE to CLDN18.2 mAb using a cleavable linker. Tissue expression of CLDN18.2 was determined by IHC assay using a CLDN18.2-specific mAb. CLDN18.2-307-mAb binds with high affinity to CLDN18.2-positive (CLDN18.2+) cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). Treatment with this CLDN18.2-mAb blocked the growth of CLDN18.2+ gastric and pancreas cancer cell line xenograft (CDX) models. Upon binding to the extracellular domain of this target, the CLDN18.2-ADC/CLDN18.2 protein was internalized and subsequently localized to the lysosomal compartment inducing complete and sustained tumor regressions in CLDN18.2+ CDXs and patient-derived pancreatic cancer xenografts (PDX). A screen of human cancer tissues, by IHC, found 58% of gastric, 60% of gastroesophageal junction, and 20% of pancreatic adenocarcinomas to be positive for membrane expression of CLDN18.2. These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase I clinical studies.
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Affiliation(s)
- Neil A O'Brien
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Martina S J McDermott
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Jun Zhang
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Ke Wei Gong
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Ming Lu
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Benjamin Hoffstrom
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Tong Luo
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Raul Ayala
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Kevin Chau
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Min Liang
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Athena M Madrid
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Timothy R Donahue
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - John A Glaspy
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Leonard Presta
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Dennis J Slamon
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
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25
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Wang Y, Gao Y, Zhang Z, Zhang Z, Wang A, Zhao K, Zhang M, Zhang S, Li M, Sun J, Guo D, Liang Z. Claudin18.2 expression in pulmonary mucinous adenocarcinoma. J Cancer Res Clin Oncol 2023; 149:12923-12929. [PMID: 37466797 DOI: 10.1007/s00432-023-05150-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/09/2023] [Indexed: 07/20/2023]
Abstract
BACKGROUND Pulmonary invasive mucinous adenocarcinoma (IMA) is a unique type of lung adenocarcinoma with a high recurrence rate and limited treatment strategies. The tight-junction-associated protein claudin18.2 is a new therapeutic target for several solid tumors. This study aimed to detect the expression of claudin18.2 in IMA and its clinicopathological association with the disease. METHODS The expression of claudin18.2 was immunohistochemically evaluated in an IMA cohort of 84 patients, who underwent partial pneumonectomy between January 2017 and December 2021. Positive staining for claudin18.2 was defined as ≥ 10% of tumor cells showing ≥ 1 + membrane staining or any ≥ 2 + membrane staining. RESULTS Claudin18.2 was detected in 76.2% (64/84) of IMA patients, significantly higher than that in non-mucinous adenocarcinoma (NMA). 46.4% (39/84) of the IMA patients met the enrollment criteria of the clinical trials of monoclonal antibodies (≥ 75% of tumor cells demonstrating ≥ 2 + staining intensity). Positive staining for claudin18.2 was significantly associated with smaller tumor size (p = 0.010), less pleural invasion (p = 0.019), and earlier pN stage (p < 0.001). Expression of claudin18.2 was not related to prognosis in multivariate analysis. CONCLUSIONS To summarize, in this study we found that claudin18.2 was remarkably highly expressed in IMA and the overexpression was associated with low invasive capacity. Thus, this protein appears to be a promising therapeutic target and deserves further investigation in IMA patients.
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Affiliation(s)
- Yuming Wang
- Department of Pathology, Molecular Pathology Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Yike Gao
- Department of Pathology, Molecular Pathology Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Zhiwen Zhang
- Department of Pathology, Molecular Pathology Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Zixin Zhang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Anqi Wang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Kun Zhao
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Miao Zhang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Sumei Zhang
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Mei Li
- Department of Pathology, Molecular Pathology Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Jian Sun
- Department of Pathology, Molecular Pathology Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, People's Republic of China.
| | - Dan Guo
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
| | - Zhiyong Liang
- Department of Pathology, Molecular Pathology Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, People's Republic of China
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26
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Bähr-Mahmud H, Ellinghaus U, Stadler CR, Fischer L, Lindemann C, Chaturvedi A, Diekmann J, Wöll S, Biermann I, Hebich B, Scharf C, Siefke M, Roth AS, Rao M, Brettschneider K, Ewen EM, Şahin U, Türeci Ö. Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody. Oncoimmunology 2023; 12:2255041. [PMID: 37860278 PMCID: PMC10583639 DOI: 10.1080/2162402x.2023.2255041] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 08/30/2023] [Indexed: 10/21/2023] Open
Abstract
IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Uğur Şahin
- BioNTech SE, Mainz, Germany
- TRON gGmbH–Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Özlem Türeci
- BioNTech SE, Mainz, Germany
- HI-TRON (Helmholtz Institute for Translational Oncology) Mainz by DKFZ, Mainz, Germany
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27
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Liang Z, Liu L, Li W, Lai H, Li L, Wu J, Zhang H, Fang C. Efficacy and safety of zolbetuximab for first-line treatment of advanced Claudin 18. 2-positive gastric or gastro-esophageal junction adenocarcinoma: a systematic review and meta-analysis of randomized controlled trials. Front Oncol 2023; 13:1258347. [PMID: 37886169 PMCID: PMC10598679 DOI: 10.3389/fonc.2023.1258347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/15/2023] [Indexed: 10/28/2023] Open
Abstract
Objective Zolbetuximab is a "first-in-class" chimeric lgG1 monoclonal antibody targeting Claudin18.2 (CLDN 18.2). In recent years, several important trials have been published showing that zolbetuximab is associated with improved prognosis in patients with advanced gastric or gastro-esophageal junction (G/GEJ) adenocarcinoma. This promises great change to the current treatment landscape. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of zolbetuximab for first-line treatment of advanced CLDN 18. 2-positive G/GEJ adenocarcinoma. Methods The following databases were searched for relevant studies: PubMed, EMBASE, and Cochrane library (updated 10 June 2023). All randomized trials comparing zolbetuximab plus chemotherapy versus first-line chemotherapy alone for first-line treatment of advanced CLDN 18. 2-positive G/GEJ adenocarcinoma were eligible for inclusion. Data were analyzed using Review Manager 5.4.1 (Cochrane collaboration software). Primary outcomes and measures included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Results This systematic review and meta-analysis included three randomized controlled studies involving 1,402 patients (699 receiving zolbetuximab plus chemotherapy and 703 receiving chemotherapy alone). Compared with chemotherapy alone, zolbetuximab plus chemotherapy significantly improved OS (HR = 0.73; 95% CI: 0.68-0.84) and PFS (HR = 0.64; 95% CI: 0.50-0.82), but did not result in a higher ORR (RR = 0.92; 95% CI: 0.82-1.03). Further analysis of CLDN 18.2 expression showed a more significant benefit for OS (HR = 0.69; 95% CI: 0.55-0.87; p = 0.002) and PFS (HR = 0.61; 95% CI: 0.44-0.84; p = 0.003) from zolbetuximab in patients with high expression, while there was significant benefit in patients with lower expression. In terms of AEs, zolbetuximab plus chemotherapy was associated with higher risk of grade 3 and higher AEs, but increased risk of nausea and vomiting were more common. Conclusion This systematic review and meta-analysis revealed that the effect of zolbetuximab plus chemotherapy was superior to that of chemotherapy alone for first-line treatment of advanced CLDN 18.2-positive G/GEJ adenocarcinoma. Thus, zolbetuximab plus chemotherapy represents a new first-line treatment for these patients. Zolbetuximab plus chemotherapy was associated with higher risk of grade 3 and higher AEs, but was generally manageable. Systematic Review Registration https://www.crd.york.ac.uk/prospero, identifier (CRD42023437126).
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Affiliation(s)
| | | | | | | | | | | | | | - Cantu Fang
- Department of Oncology, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, China
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28
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Grizzi G, Venetis K, Denaro N, Bonomi M, Celotti A, Pagkali A, Hahne JC, Tomasello G, Petrelli F, Fusco N, Ghidini M. Anti-Claudin Treatments in Gastroesophageal Adenocarcinoma: Mainstream and Upcoming Strategies. J Clin Med 2023; 12:jcm12082973. [PMID: 37109309 PMCID: PMC10142079 DOI: 10.3390/jcm12082973] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/01/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell-cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.
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Affiliation(s)
- Giulia Grizzi
- Operative Unit of Oncology, ASST of Cremona, 26100 Cremona, Italy
| | - Kostantinos Venetis
- Division of Pathology, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Nerina Denaro
- Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Maria Bonomi
- Operative Unit of Oncology, ASST of Cremona, 26100 Cremona, Italy
| | - Andrea Celotti
- Department of Surgery, ASST of Cremona, 26100 Cremona, Italy
| | - Antonia Pagkali
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Jens Claus Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Gianluca Tomasello
- Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Fausto Petrelli
- Oncology Unit, Medical Sciences Department, ASST Bergamo Ovest, 24047 Bergamo, Italy
| | - Nicola Fusco
- Division of Pathology, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Michele Ghidini
- Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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29
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Chen J, Xu Z, Hu C, Zhang S, Zi M, Yuan L, Cheng X. Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications. Front Oncol 2023; 13:1132319. [PMID: 36969060 PMCID: PMC10036590 DOI: 10.3389/fonc.2023.1132319] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Cancers of the gastrointestinal (GI) tract greatly contribute to the global cancer burden and cancer-related death. Claudin-18.2(CLDN18.2), a transmembrane protein, is a major component of tight junctions and plays an important role in the maintenance of barrier function. Its characteristic widespread expression in tumour tissues and its exposed extracellular loops make it an ideal target for researchers to develop targeted strategies and immunotherapies for cancers of the GI tract. In the present review, we focus on the expression pattern of CLDN18.2 and its clinical significance in GI cancer. We also discuss the tumour-promoting and/or tumour-inhibiting functions of CLDN18.2, the mechanisms regulating its expression, and the current progress regarding the development of drugs targeting CLDN18.2 in clinical research.
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Affiliation(s)
- Jinxia Chen
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Can Hu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Shengjie Zhang
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Mengli Zi
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Li Yuan
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- *Correspondence: Li Yuan, ; Xiangdong Cheng,
| | - Xiangdong Cheng
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- *Correspondence: Li Yuan, ; Xiangdong Cheng,
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Wu S, Xu P, Zhang F. Advances in targeted therapy for gastric cancer based on tumor driver genes. Zhejiang Da Xue Xue Bao Yi Xue Ban 2023; 53:73-83. [PMID: 38413217 PMCID: PMC10938109 DOI: 10.3724/zdxbyxb-2023-0522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/23/2024] [Indexed: 02/29/2024]
Abstract
As the understanding of the pathogenic mechanisms of gastric cancer deepens and the identification of gastric cancer driver genes advances, drugs targeting gastric cancer driver genes have been applied in clinical practice. Among them, trastuzumab, as the first targeted drug for gastric cancer, effectively inhibits the proliferation and metastasis of tumor cells by targeting overexpressed human epidermal growth factor receptor 2 (HER2). Trastuzumab has become the standard treatment for HER2-positive gastric cancer patients. Ramucirumab, on the other hand, inhibits tumor angiogenesis by targeting vascular endothelial growth factor receptor 2 (VEGFR2) and has been used as second-line therapy for advanced gastric cancer patients. In addition, bemarituzumab targets overexpressed fibroblast growth factor receptor 2 (FGFR2), while zolbetuximab targets overexpressed claudin 18.2 (CLDN18.2), significantly extending progression-free survival and overall survival in patients with gastric cancer in clinical trials. This article reviews the roles of tumor driver genes in the progression of gastric cancer, and the treatment strategies for gastric cancer primarily based on targeting HER2, VEGF, FGFR2, CLDN18.2 and MET. This provides a reference for clinical application of targeted therapy for gastric cancer.
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Affiliation(s)
- Shiying Wu
- College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
| | - Pinglong Xu
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
- Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China.
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
- Cancer Center, Zhejiang University, Hangzhou 310058, China.
| | - Fei Zhang
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
- Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China.
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Lordick F, Thuss-Patience P, Bitzer M, Maurus D, Sahin U, Türeci Ö. Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer. J Cancer Res Clin Oncol 2023:10.1007/s00432-022-04459-3. [PMID: 36607429 PMCID: PMC10356865 DOI: 10.1007/s00432-022-04459-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/01/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity. METHODS This phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. RESULTS Twenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%). CONCLUSIONS Zolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect. TRIAL REGISTRATION NCT01671774.
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Affiliation(s)
- Florian Lordick
- Department of Oncology, Gastroenterology, Hepatology, and Pulmonology, Comprehensive Cancer Center Central Germany (CCCG), University of Leipzig Medical Center, Liebigstraße 22, 04103, Leipzig, Germany.
| | - Peter Thuss-Patience
- Department of Hematology, Oncology and Tumor Immunology, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Michael Bitzer
- Department of Internal Medicine I, University Hospital, Eberhard Karls University Tuebingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany
| | - Daniel Maurus
- Ganymed Pharmaceuticals GmbH (Formerly Ganymed Pharmaceuticals AG), Mainz, Germany.,Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131, Mainz, Germany.,Ci3-Cluster of Individualized Immune Intervention, Mainz, Germany
| | - Ugur Sahin
- Translational Oncology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.,University Medical Center, Johannes Gutenberg University Mainz, Freiligrathstraße 12, 55131, Mainz, Germany.,Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131, Mainz, Germany
| | - Özlem Türeci
- Ganymed Pharmaceuticals GmbH (Formerly Ganymed Pharmaceuticals AG), Mainz, Germany.,Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131, Mainz, Germany.,Ci3-Cluster of Individualized Immune Intervention, Mainz, Germany
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Wang C, Wu N, Pei B, Ma X, Yang W. Claudin and pancreatic cancer. Front Oncol 2023; 13:1136227. [PMID: 36959784 PMCID: PMC10027734 DOI: 10.3389/fonc.2023.1136227] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/20/2023] [Indexed: 03/09/2023] Open
Abstract
Due to the lack of timely and accurate screening modalities and treatments, most pancreatic cancer (PCa) patients undergo fatal PCa progression within a short period since diagnosis. The claudin(CLDN) family is expressed specifically as tight junction structure in a variety of tumors, including PCa, and affects tumor progression by changing the cell junctions. Thus far, many of the 27 members of the claudin family, including claudin-18.2 and claudin-4, have significantly aberrantly expression in pancreatic tumors. In addition, some studies have confirmed the role of some claudin proteins in the diagnosis and treatment of pancreatic tumors. By targeting different targets of claudin protein and combining chemotherapy, further enhance tumor cell necrosis and inhibit tumor invasion and metastasis. Claudins can either promote or inhibit the development of pancreatic cancer, which indicates that the diagnosis and treatment of different kinds of claudins require to consider different biological characteristics. This literature summarizes the functional characteristics and clinical applications of various claudin proteins in Pca cells, with a focus on claudin-18.2 and claudin-4.
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Affiliation(s)
- Chen Wang
- Shanxi Medical University, Taiyuan, Shanxi, China
- Department of Gastroenterology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Na Wu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Beibei Pei
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Xiaoyan Ma
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Wenhui Yang
- Department of Gastroenterology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
- *Correspondence: Wenhui Yang,
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Development and comparison of 68Ga/ 18F/ 64Cu-labeled nanobody tracers probing Claudin18.2. Mol Ther Oncolytics 2022; 27:305-314. [PMID: 36570796 PMCID: PMC9747674 DOI: 10.1016/j.omto.2022.11.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Claudin 18.2 (CLDN18.2) is an emerging target for the treatment of gastric cancers. We aim to develop tracers to image the expression of CLDN18.2. A humanized nanobody targeting CLDN18.2 (clone hu19V3) was produced and labeled with 68Ga, 64Cu, and 18F. The tracers were investigated in subcutaneous and metastatic models established using two different mouse types (nude and Balb/c mice) and two different cell lines (CHO-CLDN18.2 and CT26-CLDN18.2). Gastric cancer patient-derived xenograft (PDX) models were further established for validation experiments. Three novel CLDN18.2-targeted tracers (i.e., [68Ga]Ga-NOTA-hu19V3, [64Cu]Cu-NOTA-hu19V3, and [18F]F-hu19V3) were developed with good radiochemical yields and excellent radiochemical purities. [68Ga]Ga-NOTA-hu19V3 immuno-positron emission tomography (immunoPET) rapidly delineated subcutaneous CHO-CLDN18.2 lesions and CT26-CLDN18.2 tumors, as well as showing excellent diagnostic value in PDX models naturally expressing CLDN18.2. While [68Ga]Ga-NOTA-hu19V3 had high kidney accumulation, [64Cu]Cu-NOTA-hu19V3 showed reduced kidney accumulation and improved image contrast at late time points. Moreover, [18F]F-hu19V3 was developed via click chemistry reaction under mild conditions and precisely disseminated CHO-CLDN18.2 lesions in the lungs. Furthermore, region of interest analysis, biodistribution study, and histopathological staining results correlated well with the in vivo imaging results. Taken together, immunoPET imaging with the three tracers can reliably visualize CLDN18.2 expression.
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Liu J, Yang H, Yin D, Jia Y, Li S, Liu Y. Expression and prognostic analysis of CLDN18 and Claudin18.2 in lung adenocarcinoma. Pathol Res Pract 2022; 238:154068. [PMID: 36007395 DOI: 10.1016/j.prp.2022.154068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/04/2022] [Accepted: 08/07/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND CLDN encodes a member of the claudin family. Claudin is a tight junction protein that is mainly involved in cell migration. Claudin family is of interest as a potential therapeutic target. Claudin18.2 is one of its important isoforms and is mainly expressed in the stomach. Its expression and prognosis in lung adenocarcinoma remain unknown. The aim of this study was to investigate the correlation between CLDN18 and claudin18.2 expression and prognosis in lung adenocarcinoma. METHODS Two cohorts were introduced in this study: one from The Cancer Genome Atlas (TCGA) CLDN18 mRNA public data (TCGA-LUAD, N = 551); the other from 1079 cases of lung adenocarcinoma diagnosed at the Fourth Hospital of Hebei Medical University, China, with immunohistochemical (IHC) detection of claudin18.2 in tissue microarrays. the IHC-positive cases were again verified by fluorescence in situ hybridization (FISH). RESULTS The mRNA expression of CLDN18 was significantly lower in lung adenocarcinoma tissues than in normal lung tissues (P < 0.05). Among 1079 Chinese lung adenocarcinoma cases, the overall positive rate of IHC for Claudin18.2 was 7.78% (84/1079). Among those positive for IHC, the positive rate of FISH was 11.9% (10/84), which accounted for 0.9% of the total number of cases (10/1079). To explore the best scoring scheme for Claudin 18.2, we used a four-group (IHC4) and two-group (IHC2) scoring method for evaluation. We found that IHC4 better explained Claudin 18.2 expression and helped us to find specific differences in clinical factors for weak, moderate and strong Claudin 18.2 expression. This difference was not discernible in the IHC2 score. By survival analysis, we found that Claudin 18.2 (IHC4) was able to stratify the prognosis of lung adenocarcinoma patients, with strongly positive patients having a better prognosis than the other subgroups (p < 0.05). We also found that patients with EGFR wild type or PD-L1 < 1% accompanied by strong positive claudin18.2 had a significantly better prognosis than other subgroups (P < 0.05). CONCLUSION Claudin18.2 (IHC4) better reveals the clinical and prognostic characteristics of patients with lung adenocarcinoma. Patients with EGFR wild type and PD-L1 < 1% have a better prognosis and partially overlap with claudin18.2 expression, so claudin18.2 may also be an important biomarker for lung adenocarcinoma testing, which is particularly important for EGFR wild type and PD-L1 < 1%.
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Affiliation(s)
- Junying Liu
- Department of pathology, The Fourth Affiliated Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang 050011, PR China
| | - Huichai Yang
- Department of pathology, The Fourth Affiliated Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang 050011, PR China
| | - Danjing Yin
- Department of pathology, The Fourth Affiliated Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang 050011, PR China
| | - Ying Jia
- Department of pathology, The Fourth Affiliated Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang 050011, PR China
| | - Shi Li
- Department of pathology, The Fourth Affiliated Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang 050011, PR China
| | - Yueping Liu
- Department of pathology, The Fourth Affiliated Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang 050011, PR China.
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Wang X, Zhang CS, Dong XY, Hu Y, Duan BJ, Bai J, Wu YY, Fan L, Liao XH, Kang Y, Zhang P, Li MY, Xu J, Mao ZJ, Liu HT, Zhang XL, Tian LF, Li EX. Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma. World J Gastrointest Oncol 2022; 14:1252-1264. [PMID: 36051096 PMCID: PMC9305579 DOI: 10.4251/wjgo.v14.i7.1252] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/22/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.
AIM To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.
METHODS The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated.
RESULTS The gene expression of CLDN18 was statistically higher (P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, 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.
CONCLUSION CLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC.
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Affiliation(s)
- Xi Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Medical Oncology, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - Cheng-Sheng Zhang
- Department of Cancer Precision Medicine, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Xu-Yuan Dong
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yuan Hu
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Bao-Jun Duan
- Department of Medical Oncology, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - Jun Bai
- Department of Medical Oncology, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - Yin-Ying Wu
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Lin Fan
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Xin-Hua Liao
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Ye Kang
- Department of Cancer Precision Medicine, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Peng Zhang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Meng-Yang Li
- Department of Cancer Precision Medicine, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - 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
| | - Zhi-Jun Mao
- 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
| | - Xiao-Long Zhang
- Department of General Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - Li-Fei Tian
- Department of General Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China
| | - En-Xiao Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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Cao W, Xing H, Li Y, Tian W, Song Y, Jiang Z, Yu J. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res 2022; 10:38. [PMID: 35642043 PMCID: PMC9153115 DOI: 10.1186/s40364-022-00385-1] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/16/2022] [Indexed: 12/18/2022] Open
Abstract
The claudin18.2 (CLDN18.2) protein, an isoform of claudin18, a member of the tight junction protein family, is a highly selective biomarker with limited expression in normal tissues and often abnormal expression during the occurrence and development of various primary malignant tumors, such as gastric cancer/gastroesophageal junction (GC/GEJ) cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer and non-small-cell lung cancer. CLDN18.2 participates in the proliferation, differentiation and migration of tumor cells. Recent studies have identified CLDN18.2 expression as a potential specific marker for the diagnosis and treatment of these tumors. With its specific expression pattern, CLDN18.2 has become a unique molecule for targeted therapy in different cancers, especially in GC; for example, agents such as zolbetuximab (claudiximab, IMAB362), a monoclonal antibody (mAb) against CLDN18.2, have been developed. In this review, we outline recent advances in the development of immunotherapy strategies targeting CLDN18.2, including monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), chimeric antigen receptor T (CAR-T) cells redirected to target CLDN18.2, and antibody–drug conjugates (ADCs).
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Affiliation(s)
- Weijie Cao
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Haizhou Xing
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yingmei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Wenliang Tian
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yongping Song
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Zhongxing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Jifeng Yu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Claudins and Gastric Cancer: An Overview. Cancers (Basel) 2022; 14:cancers14020290. [PMID: 35053454 PMCID: PMC8773541 DOI: 10.3390/cancers14020290] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/02/2022] [Accepted: 01/03/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Gastric cancer (GC) is one of the most common cancers and the third leading cause of cancer deaths worldwide, with a high frequency of recurrence and metastasis, and a poor prognosis. This review presents novel biological and clinical significance of claudin (CLDN) expression in GC, especially CLDN18, and clinical trials centered around CLDN18.2. It also presents new findings for other CLDNs. Abstract Despite recent improvements in diagnostic ability and treatment strategies, advanced gastric cancer (GC) has a high frequency of recurrence and metastasis, with poor prognosis. To improve the treatment results of GC, the search for new treatment targets from proteins related to epithelial–mesenchymal transition (EMT) and cell–cell adhesion is currently being conducted. EMT plays an important role in cancer metastasis and is initiated by the loss of cell–cell adhesion, such as tight junctions (TJs), adherens junctions, desmosomes, and gap junctions. Among these, claudins (CLDNs) are highly expressed in some cancers, including GC. Abnormal expression of CLDN1, CLDN2, CLDN3, CLDN4, CLDN6, CLDN7, CLDN10, CLDN11, CLDN14, CLDN17, CLDN18, and CLDN23 have been reported. Among these, CLDN18 is of particular interest. In The Cancer Genome Atlas, GC was classified into four new molecular subtypes, and CLDN18–ARHGAP fusion was observed in the genomically stable type. An anti-CLDN18.2 antibody drug was recently developed as a therapeutic drug for GC, and the results of clinical trials are highly predictable. Thus, CLDNs are highly expressed in GC as TJs and are expected targets for new antibody drugs. Herein, we review the literature on CLDNs, focusing on CLDN18 in GC.
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Zuo J, Tong Y, Yang Y, Wang Y, Yue D. Claudin-18 expression under hyperoxia in neonatal lungs of bronchopulmonary dysplasia model rats. Front Pediatr 2022; 10:916716. [PMID: 36299696 PMCID: PMC9589239 DOI: 10.3389/fped.2022.916716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 09/21/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Bronchopulmonary dysplasia (BPD) is characterized by impaired alveolar and microvascular development. Claudin-18 is the only known lung-specific tight junction protein affecting the development and transdifferentiation of alveolar epithelium. OBJECTIVE We aimed to explore the changes in the expression of claudin-18, podoplanin, SFTPC, and the canonical WNT pathway, in a rat model of hyperoxia-induced BPD, and to verify the regulatory relationship between claudin-18 and the canonical WNT pathway by cell experiments. METHODS A neonatal rat and cell model of BPD was established by exposing to hyperoxia (85%). Hematoxylin and eosin (HE) staining was used to confirm the establishment of the BPD model. The mRNA levels were assessed using quantitative real-time polymerase chain reaction(qRT-PCR). Protein expression levels were determined using western blotting, immunohistochemical staining, and immunofluorescence. RESULTS As confirmed by HE staining, the neonatal rat model of BPD was successfully established. Compared to that in the control group, claudin-18 and claudin-4 expression decreased in the hyperoxia group. Expression of β-catenin in the WNT signaling pathway decreased, whereas that of p-GSK-3β increased. Expression of the AEC II marker SFTPC initially decreased and then increased, whereas that of the AEC I marker podoplanin increased on day 14 (P < 0.05). Similarly, claudin-18, claudin-4, SFTPC and β-catenin were decreased but podoplanin was increased when AEC line RLE-6TN exposed to 85% hyperoxia. And the expression of SFTPC was increased, the podoplanin was decreased, and the WNT pathway was upregulated when claudin-18 was overexpressed. CONCLUSIONS Claudin-18 downregulation during hyperoxia might affect lung development and maturation, thereby resulting in hyperoxia-induced BPD. Additionally, claudin-18 is associated with the canonical WNT pathway and AECs transdifferentiation.
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Affiliation(s)
- Jingye Zuo
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yajie Tong
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuting Yang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yirui Wang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Dongmei Yue
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
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Pellino A, Brignola S, Riello E, Niero M, Murgioni S, Guido M, Nappo F, Businello G, Sbaraglia M, Bergamo F, Spolverato G, Pucciarelli S, Merigliano S, Pilati P, Cavallin F, Realdon S, Farinati F, Dei Tos AP, Zagonel V, Lonardi S, Loupakis F, Fassan M. Association of CLDN18 Protein Expression with Clinicopathological Features and Prognosis in Advanced Gastric and Gastroesophageal Junction Adenocarcinomas. J Pers Med 2021; 11:1095. [PMID: 34834447 PMCID: PMC8624955 DOI: 10.3390/jpm11111095] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/11/2021] [Accepted: 10/22/2021] [Indexed: 12/16/2022] Open
Abstract
The tight junction protein claudin-18 (CLDN18), is often expressed in various cancer types including gastric (GC) and gastroesophageal adenocarcinomas (GECs). In the last years, the isoform CLDN18.2 emerged as a potential drug target in metastatic GCs, leading to the development of monoclonal antibodies against this protein. CLDN18.2 is the dominant isoform of CLDN18 in normal gastric and gastric cancer tissues. In this work, we evaluated the immunohistochemical (IHC) profile of CLDN18 and its correlation with clinical and histopathological features including p53, E-cadherin, MSH2, MSH6, MLH1, PMS2, HER2, EBER and PD-L1 combined positive score, in a large real-world and mono-institutional series of advanced GCs (n = 280) and GECs (n = 70). The association of IHC results with survival outcomes was also investigated. High membranous CLDN18 expression (2+ and 3+ intensity ≥75%) was found in 117/350 (33.4%) samples analyzed. CLDN18 expression correlated with age <70 (p = 0.0035), positive EBV status (p = 0.002), high stage (III, IV) at diagnosis (p = 0.003), peritoneal involvement (p < 0.001) and lower incidence of liver metastases (p = 0.013). CLDN18 did not correlate with overall survival. The predictive value of response of CLDN18 to targeted agents is under investigation in several clinical trials and further studies will be needed to select patients who could benefit from these therapies.
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Affiliation(s)
- Antonio Pellino
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Stefano Brignola
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
- Department of Pathology, Azienda ULSS 2 Marca Trevigiana, 31100 Treviso, Italy;
| | - Erika Riello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
| | - Monia Niero
- Department of Pathology, Azienda ULSS 2 Marca Trevigiana, 31100 Treviso, Italy;
| | - Sabina Murgioni
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Maria Guido
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
- Department of Pathology, Azienda ULSS 2 Marca Trevigiana, 31100 Treviso, Italy;
| | - Floriana Nappo
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Gianluca Businello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
| | - Marta Sbaraglia
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
| | - Francesca Bergamo
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Gaya Spolverato
- 1st Surgery Unit, Department of Surgical, Oncological, and Gastroenterological Sciences (DISCOG), University of Padua, 35122 Padua, Italy; (G.S.); (S.P.)
| | - Salvatore Pucciarelli
- 1st Surgery Unit, Department of Surgical, Oncological, and Gastroenterological Sciences (DISCOG), University of Padua, 35122 Padua, Italy; (G.S.); (S.P.)
| | - Stefano Merigliano
- 3rd Surgery Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35122 Padua, Italy;
| | - Pierluigi Pilati
- Surgery Unit, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 31033 Castelfranco Veneto, Italy;
| | | | - Stefano Realdon
- Gastroenterology Unit, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy;
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgical, Oncological, and Gastroenterological Sciences (DISCOG), University of Padua, 35122 Padua, Italy;
| | - Angelo Paolo Dei Tos
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
| | - Vittorina Zagonel
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Sara Lonardi
- Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy;
| | - Fotios Loupakis
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy; (A.P.); (S.M.); (F.N.); (F.B.); (V.Z.); (F.L.)
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy; (S.B.); (E.R.); (M.G.); (G.B.); (M.S.); (A.P.D.T.)
- Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy
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Sato K, Matsumoto I, Suzuki K, Tamura A, Shiraishi A, Kiyonari H, Kasamatsu J, Yamamoto H, Miyasaka T, Tanno D, Miyahara A, Zong T, Kagesawa T, Oniyama A, Kawamura K, Kitai Y, Umeki A, Kanno E, Tanno H, Ishii K, Tsukita S, Kawakami K. Deficiency of lung-specific claudin-18 leads to aggravated infection with Cryptococcus deneoformans through dysregulation of the microenvironment in lungs. Sci Rep 2021; 11:21110. [PMID: 34702961 PMCID: PMC8548597 DOI: 10.1038/s41598-021-00708-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/15/2021] [Indexed: 12/25/2022] Open
Abstract
Cryptococcus deneoformans is an opportunistic fungal pathogen that infects the lungs via airborne transmission and frequently causes fatal meningoencephalitis. Claudins (Cldns), a family of proteins with 27 members found in mammals, form the tight junctions within epithelial cell sheets. Cldn-4 and 18 are highly expressed in airway tissues, yet the roles of these claudins in respiratory infections have not been clarified. In the present study, we analyzed the roles of Cldn-4 and lung-specific Cldn-18 (luCldn-18) in host defense against C. deneoformans infection. luCldn-18-deficient mice exhibited increased susceptibility to pulmonary infection, while Cldn-4-deficient mice had normal fungal clearance. In luCldn-18-deficient mice, production of cytokines including IFN-γ was significantly decreased compared to wild-type mice, although infiltration of inflammatory cells including CD4+ T cells into the alveolar space was significantly increased. In addition, luCldn-18 deficiency led to high K+ ion concentrations in bronchoalveolar lavage fluids and also to alveolus acidification. The fungal replication was significantly enhanced both in acidic culture conditions and in the alveolar spaces of luCldn-18-deficient mice, compared with physiological pH conditions and those of wild-type mice, respectively. These results suggest that luCldn-18 may affect the clinical course of cryptococcal infection indirectly through dysregulation of the alveolar space microenvironment.
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Affiliation(s)
- Ko Sato
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. .,Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
| | - Ikumi Matsumoto
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Koya Suzuki
- Laboratory of Biological Science and Laboratory of Biosciences, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.,Research Institute for Diseases of Old Age and Department of Clinical Laboratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Atsushi Tamura
- Laboratory of Biological Science and Laboratory of Biosciences, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
| | - Aki Shiraishi
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Jun Kasamatsu
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hideki Yamamoto
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.,Center for Transdisciplinary Research, Institute of Research Promotion, Niigata University, Niigata, Japan
| | - Tomomitsu Miyasaka
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
| | - Daiki Tanno
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.,Department of Clinical Laboratory, Fukushima Medical University, Fukushima, Japan
| | - Anna Miyahara
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tong Zong
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Takafumi Kagesawa
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Akiho Oniyama
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Kotone Kawamura
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yuki Kitai
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Aya Umeki
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hiromasa Tanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Sachiko Tsukita
- Laboratory of Biological Science and Laboratory of Biosciences, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
| | - Kazuyoshi Kawakami
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.,Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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Siddiqui AZ, Almhanna K. Beyond Chemotherapy, PD-1, and HER-2: Novel Targets for Gastric and Esophageal Cancer. Cancers (Basel) 2021; 13:4322. [PMID: 34503132 PMCID: PMC8430615 DOI: 10.3390/cancers13174322] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/14/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Together, gastric cancer and esophageal cancer (EC) possess two of the highest incidence rates amongst all cancers. They exhibit poor prognoses in which the 5-year survival rate is dismal. In addition to cytotoxic chemotherapy, treatment efforts have been geared toward targeting human epidermal growth factor receptor 2 (HER-2), vascular endothelial growth factor (VEGF), and programmed death ligand-1 (PD-1). Although ample success has been recorded with these agents, gastric and esophageal cancer remain lethal, and further research into potential treatment alternatives is needed. In this article, we will review some of the targets at the forefront of investigation such as claudin, Dickkopf-related protein 1 (DKK-1), fibroblast growth factor receptor (FGFR), and matrix metalloproteinases (MMPs). These innovative target pathways are in the midst of clinical trials to be implemented in the treatment algorithm for this patient population. Ultimately, exploiting the oncogenic tendencies of these potential biomarkers creates an opportunity for precise treatment and improved prognosis for these cancers. Lastly, research aimed toward reversing PD-1 antibodies resistance by combining it with other novel agents or other treatment modalities is underway in order to expand existing treatment options for this patient population.
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Affiliation(s)
- Ali Zubair Siddiqui
- University of Mississippi Medical Center, University of Mississippi School of Medicine, Jackson, MS 39216, USA
| | - Khaldoun Almhanna
- The Brown University Oncology Research Group, The Rhode Island Hospital/Lifespan Cancer Institute, Providence, RI 02903, USA;
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Zuo JY, Tong YJ, Yue DM. [A review on the effect of Claudin-18 on bronchopulmonary dysplasia in preterm infants]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2021; 23:542-547. [PMID: 34020748 PMCID: PMC8140329 DOI: 10.7499/j.issn.1008-8830.2101025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/19/2021] [Indexed: 06/12/2023]
Abstract
Bronchopulmonary dysplasia (BPD) has the main manifestations of pulmonary edema in the early stage and characteristic alveolar obstruction and microvascular dysplasia in the late stage, which may be caused by structural and functional destruction of the lung epithelial barrier. The Claudin family is the main component of tight junction and plays an important role in regulating the permeability of paracellular ions and solutes. Claudin-18 is the only known tight junction protein solely expressed in the lung. The lack of Claudin-18 can lead to barrier dysfunction and impaired alveolar development, and the knockout of Claudin-18 can cause characteristic histopathological changes of BPD. This article elaborates on the important role of Claudin-18 in the development and progression of BPD from the aspects of lung epithelial permeability, alveolar development, and progenitor cell homeostasis, so as to provide new ideas for the pathogenesis and clinical treatment of BPD.
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Affiliation(s)
- Jing-Ye Zuo
- Department of Neonatology, Shengjing Hospital, China Medical University, Shenyang 110004, China
| | - Ya-Jie Tong
- Department of Neonatology, Shengjing Hospital, China Medical University, Shenyang 110004, China
| | - Dong-Mei Yue
- Department of Neonatology, Shengjing Hospital, China Medical University, Shenyang 110004, China
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Sahin U, Türeci Ö, Manikhas G, Lordick F, Rusyn A, Vynnychenko I, Dudov A, Bazin I, Bondarenko I, Melichar B, Dhaene K, Wiechen K, Huber C, Maurus D, Arozullah A, Park JW, Schuler M, Al-Batran SE. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol 2021; 32:609-619. [PMID: 33610734 DOI: 10.1016/j.annonc.2021.02.005] [Citation(s) in RCA: 232] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.
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Affiliation(s)
- U Sahin
- Department of Experimental and Translational Oncology, TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Department of Oncology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany
| | - Ö Türeci
- Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; CI3 - Cluster of Individualized Immune Intervention, Mainz, Germany; formerly of Ganymed Pharmaceuticals GmbH
| | - G Manikhas
- Department of Oncology, City Clinical Oncology Center, St. Petersburg, Russia
| | - F Lordick
- Department of Medicine II and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany
| | - A Rusyn
- Department of Oncology, Transcarpathian Regional Clinical Oncological Center, Uzhhorod, Ukraine
| | - I Vynnychenko
- Sumy State University, Sumy Regional Clinical Oncology Center, Oncothoracic Department, Sumy, Ukraine
| | - A Dudov
- Department of Oncology, Acibadem City Clinic Mladost, Sofia, Bulgaria
| | - I Bazin
- Department of Clinical Pharmacology and Chemotherapy, Russian Oncology Research Center n. a. N.N. Blokhin, Moscow, Russia
| | - I Bondarenko
- Dnipropetrovsk Medical Academy, City Multispecialty Clinical Hospital #4, Department of Chemotherapy, Dnipropetrovsk, Ukraine
| | - B Melichar
- Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic
| | - K Dhaene
- MD Dhaene Pathology Lab BVBA, Destelbergen, Belgium
| | - K Wiechen
- Department of Pathology, Klinikum Worms GmbH, Institute for Pathology, Worms, Germany
| | - C Huber
- Department of Experimental and Translational Oncology, TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; CI3 - Cluster of Individualized Immune Intervention, Mainz, Germany; formerly of Ganymed Pharmaceuticals GmbH
| | - D Maurus
- Formerly of Ganymed Pharmaceuticals GmbH, Mainz, Germany
| | - A Arozullah
- Astellas Pharma Global Development, Inc., Northbrook, USA
| | - J W Park
- Astellas Pharma Global Development, Inc., Northbrook, USA
| | - M Schuler
- West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - S-E Al-Batran
- Institute of Clinical Cancer Research (IKF) at Krankenhaus Nordwest, Frankfurt, Germany.
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Lü P, Qiu S, Pan Y, Yu F, Chen K. Preclinical Chimeric Antibody Chimeric Antigen Receptor T Cell Progress in Digestive System Cancers. Cancer Biother Radiopharm 2021; 36:307-315. [PMID: 33481647 DOI: 10.1089/cbr.2020.4089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Digestive system cancers, including hepatocellular carcinoma, colorectal and gastric tumors, are characterized by high rates of incidence and mortality. Digestive cancers are difficult to diagnose during the early stages, and the side effects of chemotherapy are often severe and may outweigh the therapeutic benefits. Chimeric antibody chimeric antigen receptor T cell (CAR-T) therapy, a novel immunotherapy, has achieved excellent results for the treatment of hematological tumors. However, CAR-T treatment of solid tumors has struggled due to a lack of target specificity, a difficult tumor microenvironment, and T cell homing. Despite the challenges, CAR-T treatment of digestive cancers is progressing. Combining CAR-T with other targets and/or modifying the CAR may represent the most promising approaches for future treatment of digestive cancers.
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Affiliation(s)
- Peng Lü
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China.,School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Songlin Qiu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Ye Pan
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Feng Yu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Keping Chen
- Institute of Life Sciences, Jiangsu University, Zhenjiang, China
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45
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Zhu G, Foletti D, Liu X, Ding S, Melton Witt J, Hasa-Moreno A, Rickert M, Holz C, Aschenbrenner L, Yang AH, Kraynov E, Evering W, Obert L, Lee C, Sai T, Mistry T, Lindquist KC, Van Blarcom T, Strop P, Chaparro-Riggers J, Liu SH. Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer. Sci Rep 2019; 9:8420. [PMID: 31182754 PMCID: PMC6557842 DOI: 10.1038/s41598-019-44874-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 05/27/2019] [Indexed: 02/07/2023] Open
Abstract
Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression is limited to the epithelium of the stomach. The restricted expression makes it a potential drug target for the treatment of gastric and pancreatic adenocarcinoma, as evidenced by efforts to target CLDN18.2 via naked antibody and CAR-T modalities. Herein we describe CLDN18.2-targeting via a CD3-bispecific and an antibody drug conjugate and the characterization of these potential therapeutic molecules in efficacy and preliminary toxicity studies. Anti-hCLDN18.2 ADC, CD3-bispecific and diabody, targeting a protein sequence conserved in rat, mouse and monkey, exhibited in vitro cytotoxicity in BxPC3/hCLDN18.2 (IC50 = 1.52, 2.03, and 0.86 nM) and KATO-III/hCLDN18.2 (IC50 = 1.60, 0.71, and 0.07 nM) respectively and inhibited tumor growth of pancreatic and gastric patient-derived xenograft tumors. In a rat exploratory toxicity study, the ADC was tolerated up to 10 mg/kg. In a preliminary assessment of tolerability, the anti-CLDN18.2 diabody (0.34 mg/kg) did not produce obvious signs of toxicity in the stomach of NSG mice 4 weeks after dosing. Taken together, our data indicate that targeting CLDN18.2 with an ADC or bispecific modality could be a valid therapeutic approach for the treatment of gastric and pancreatic cancer.
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Affiliation(s)
- Guoyun Zhu
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.
| | - Davide Foletti
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,23 and Me, 349 Oyster Point Blvd, South San Francisco, CA, 94080, USA
| | - Xiaohui Liu
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA
| | - Sheng Ding
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Gilead Sciences, 333 Lakeside Drive, Foster City, CA, 94404, USA
| | - Jody Melton Witt
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Grifols Diagnostic Solutions, 6455 Christie Ave B-334C, Emeryville, CA, 94608, USA
| | - Adela Hasa-Moreno
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Kodiak Sciences Inc., 2631 Hanover St, Palo Alto, CA, 94304, USA
| | - Mathias Rickert
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Applied Molecular Transport, 1 Tower Place, Suite 850, South San Francisco, CA, 94080, USA
| | - Charles Holz
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Grifols Diagnostic Solutions, 6455 Christie Ave B-334C, Emeryville, CA, 94608, USA
| | - Laura Aschenbrenner
- Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Dr., San Diego, CA, 92121, USA.,Covance Inc. Early Phase Development Solutions, 3301 Kinsman Blvd, Madison, WI, 53704, USA
| | - Amy H Yang
- Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Dr., San Diego, CA, 92121, USA
| | - Eugenia Kraynov
- BioMedicine Design, Pfizer Worldwide Research and Development, 10646 Science Center Dr., San Diego, CA, 92121, USA
| | - Winston Evering
- Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Dr., San Diego, CA, 92121, USA
| | - Leslie Obert
- Drug Safety Research and Development, Pfizer Worldwide Research and Development, 280 Shennecossett Rd, Groton, CT, 06340, USA.,GSK, 1250 South Collegeville Road, Collegeville, PA, 19426, USA
| | - Chenyu Lee
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Alector, 151 Oyster Point Blvd #300, South San Francisco, CA, 94080, USA
| | - Tao Sai
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA
| | - Tina Mistry
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA
| | - Kevin C Lindquist
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA
| | - Thomas Van Blarcom
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Allogene Therapeutics, 210 E. Grand Avenue, South San Francisco, CA, 94080, USA
| | - Pavel Strop
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Bristol-Myers Squibb, 700 Bay Rd suite A, Redwood City, CA, 94063, USA
| | - Javier Chaparro-Riggers
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA
| | - Shu-Hui Liu
- Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA.,Multitude Therapeutics, Abmart, 3698 Haven Avenue Suite A, Redwood City, CA, 94063, USA
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Luo J, Chimge NO, Zhou B, Flodby P, Castaldi A, Firth AL, Liu Y, Wang H, Yang C, Marconett CN, Crandall ED, Offringa IA, Frenkel B, Borok Z. CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro. Int J Cancer 2018; 143:3169-3180. [PMID: 30325015 PMCID: PMC6263834 DOI: 10.1002/ijc.31734] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 05/21/2018] [Accepted: 06/11/2018] [Indexed: 12/18/2022]
Abstract
Claudins are a family of transmembrane proteins integral to the structure and function of tight junctions (TJ). Disruption of TJ and alterations in claudin expression are important features of invasive and metastatic cancer cells. Expression of CLDN18.1, the lung-specific isoform of CLDN18, is markedly decreased in lung adenocarcinoma (LuAd). Furthermore, we recently observed that aged Cldn18 -/- mice have increased propensity to develop LuAd. We now demonstrate that CLDN18.1 expression correlates inversely with promoter methylation and with LuAd patient mortality. In addition, when restored in LuAd cells that have lost expression, CLDN18.1 markedly attenuates malignant properties including xenograft tumor growth in vivo as well as cell proliferation, migration, invasion and anchorage-independent colony formation in vitro. Based on high throughput analyses of Cldn18 -/- murine lung alveolar epithelial type II cells, as well as CLDN18.1-repleted human LuAd cells, we hypothesized and subsequently confirmed by Western analysis that CLDN18.1 inhibits insulin-like growth factor-1 receptor (IGF-1R) and AKT phosphorylation. Consistent with recent data in Cldn18 -/- knockout mice, expression of CLDN18.1 in human LuAd cells also decreased expression of transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) and their target genes, contributing to its tumor suppressor activity. Moreover, analysis of LuAd cells in which YAP and/or TAZ are silenced with siRNA suggests that inhibition of TAZ, and possibly YAP, is also involved in CLDN18.1-mediated AKT inactivation. Taken together, these data indicate a tumor suppressor role for CLDN18.1 in LuAd mediated by a regulatory network that encompasses YAP/TAZ, IGF-1R and AKT signaling.
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Affiliation(s)
- Jiao Luo
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
| | - Nyam-Osor Chimge
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
| | - Beiyun Zhou
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Per Flodby
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
| | - Alessandra Castaldi
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
| | - Amy L. Firth
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yixin Liu
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
| | - Hongjun Wang
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
| | - Chenchen Yang
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Crystal N. Marconett
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Edward D. Crandall
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA
| | - Ite A. Offringa
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Baruch Frenkel
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Zea Borok
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, USA
- Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA
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47
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Alessandrini L, Manchi M, De Re V, Dolcetti R, Canzonieri V. Proposed Molecular and miRNA Classification of Gastric Cancer. Int J Mol Sci 2018; 19:E1683. [PMID: 29882766 PMCID: PMC6032377 DOI: 10.3390/ijms19061683] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with GC for shaping prognosis and treatment planning. Based on new knowledge of molecular pathways associated with different aspect of GC, new pathogenetic classifications for GC have been and continue to be proposed. These novel classifications create a new paradigm in the definition of cancer biology and allow the identification of relevant GC genomic subsets by using different techniques such as genomic screenings, functional studies and molecular or epigenetic characterization. An improved prognostic classification for GC is essential for the development of a proper therapy for a proper patient population. The aim of this review is to discuss the state-of-the-art on combining histological and molecular classifications of GC to give an overview of the emerging therapeutic possibilities connected to the latest discoveries regarding GC.
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Affiliation(s)
- Lara Alessandrini
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Melissa Manchi
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Valli De Re
- Immunopathology and Cancer Biomarkers, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Riccardo Dolcetti
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
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48
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Zhou B, Flodby P, Luo J, Castillo DR, Liu Y, Yu FX, McConnell A, Varghese B, Li G, Chimge NO, Sunohara M, Koss MN, Elatre W, Conti P, Liebler JM, Yang C, Marconett CN, Laird-Offringa IA, Minoo P, Guan K, Stripp BR, Crandall ED, Borok Z. Claudin-18-mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis. J Clin Invest 2018; 128:970-984. [PMID: 29400695 DOI: 10.1172/jci90429] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 12/05/2017] [Indexed: 12/19/2022] Open
Abstract
Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.
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Affiliation(s)
- Beiyun Zhou
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and.,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Per Flodby
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and
| | - Jiao Luo
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and
| | - Dan R Castillo
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and
| | - Yixin Liu
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and
| | - Fa-Xing Yu
- Department of Pharmacology and Moores Cancer Center, UCSD, La Jolla, California, USA.,Childrens Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Alicia McConnell
- Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | - Guanglei Li
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and
| | - Nyam-Osor Chimge
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and
| | - Mitsuhiro Sunohara
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and
| | | | | | | | - Janice M Liebler
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and
| | - Chenchen Yang
- Department of Surgery.,Department of Biochemistry and Molecular Medicine, and
| | - Crystal N Marconett
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.,Department of Surgery
| | - Ite A Laird-Offringa
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.,Department of Surgery.,Department of Biochemistry and Molecular Medicine, and
| | - Parviz Minoo
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Kunliang Guan
- Department of Pharmacology and Moores Cancer Center, UCSD, La Jolla, California, USA
| | - Barry R Stripp
- Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Edward D Crandall
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and.,Department of Pathology.,Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA
| | - Zea Borok
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.,Hastings Center for Pulmonary Research.,Will Rogers Institute Pulmonary Research Center, and.,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.,Department of Biochemistry and Molecular Medicine, and
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49
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Garattini SK, Basile D, Cattaneo M, Fanotto V, Ongaro E, Bonotto M, Negri FV, Berenato R, Ermacora P, Cardellino GG, Giovannoni M, Pella N, Scartozzi M, Antonuzzo L, Silvestris N, Fasola G, Aprile G. Molecular classifications of gastric cancers: Novel insights and possible future applications. World J Gastrointest Oncol 2017; 9:194-208. [PMID: 28567184 PMCID: PMC5434387 DOI: 10.4251/wjgo.v9.i5.194] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 12/04/2016] [Accepted: 03/17/2017] [Indexed: 02/05/2023] Open
Abstract
Despite some notable advances in the systemic management of gastric cancer (GC), the prognosis of patients with advanced disease remains overall poor and their chance of cure is anecdotic. In a molecularly selected population, a median overall survival of 13.8 mo has been reached with the use of human epidermal growth factor 2 (HER2) inhibitors in combination with chemotherapy, which has soon after become the standard of care for patients with HER2-overexpressing GC. Moreover, oncologists have recognized the clinical utility of conceiving cancers as a collection of different molecularly-driven entities rather than a single disease. Several molecular drivers have been identified as having crucial roles in other tumors and new molecular classifications have been recently proposed for gastric cancer as well. Not only these classifications allow the identification of different tumor subtypes with unique features, but also they serve as springboard for the development of different therapeutic strategies. Hopefully, the application of standard systemic chemotherapy, specific targeted agents, immunotherapy or even surgery in specific cancer subgroups will help maximizing treatment outcomes and will avoid treating patients with minimal chance to respond, therefore diluting the average benefit. In this review, we aim at elucidating the aspects of GC molecular subtypes, and the possible future applications of such molecular analyses.
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50
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Claudin-18 inhibits cell proliferation and motility mediated by inhibition of phosphorylation of PDK1 and Akt in human lung adenocarcinoma A549 cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1170-8. [PMID: 26919807 DOI: 10.1016/j.bbamcr.2016.02.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 02/01/2016] [Accepted: 02/22/2016] [Indexed: 11/20/2022]
Abstract
Abnormal expression of claudin subtypes has been reported in various cancers. However, the pathological role of each claudin has not been clarified in detail. Claudin-18 was absent in human non-small cell and small cell lung cancers, although it is expressed in normal lung tissues. Here, we examined the effect of claudin-18 expression on the expression of junctional proteins, cell proliferation, and cell motility using human lung adenocarcinoma A549 cells. Real-time PCR and western blotting showed that exogenous expression of claudin-18 had no effect on the expression of junctional proteins including claudin-1, zonula occludens-1 (ZO-1), occludin, and E-cadherin. Claudin-18 was mainly distributed in cell-cell contact areas concomitant with ZO-1. Cell proliferation was significantly decreased at 48 and 72h after seeding of claudin 18-expressing cells. Claudin-18 suppressed cell motility, whereas it increased cell death in anoikis. Claudin-18 decreased phosphorylated (p)-3-phosphoinositide-dependent protein kinase-1 (PDK1) and p-Akt levels without affecting p-epidermal growth factor receptor and p-phosphatidylinositol-3 kinase (PI3K) levels. Furthermore, claudin-18 was bound with PDK1 and suppressed the nuclear localization of PDK1. We suggest that claudin-18 suppresses the abnormal proliferation and motility of lung epithelial cells mediated by inhibition of the PI3K/PDK1/Akt signaling pathway.
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