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Recent years have seen an increasing research towards immunotherapy for gastrointestinal cancers (GICs), such as monoclonal antibodies, bispecific antibodies, and CAR-T cell therapy. Some targets identification lies at the heart of GIC treatment, like EGFR, HER-2, PD-1, MET, CTLA-4, VEGF, DDR1, LAG-3, MUC1, TIGIT, CLDN18.2. Novel therapeutic targets are still emerging. It's exciting that Arbele is testing the CDH17 monoclonal antibody (ARB102) and bispecific antibody CDH17/CD3 (ARB202) to treat pancreatic and bile duct cancer. Boehringer Ingelheim developed a new bispecific antibody CDH17/TRAILR2 (BI 905711) for GICs.
Moreover, another study suggested that VHH1-CAR T-cell (CDH17 CARTs) eradicated CDH17-expressing neuroendocrine tumors (NETs) and gastric, pancreatic, and colorectal cancers in either tumor xenograft or autochthonous mouse models. Notably, CDH17 CARTs do not attack normal intestinal epithelial cells, which also express CDH17. All in all, CDH17, as a novel member of the cadherin superfamily, offers new insights into immunotherapy strategies for solid tumors, particularly gastrointestinal cancers.
Cadherins are a large superfamily of cell adhesion molecules. Cadherins form a superfamily with at least six subfamilies: classical cadherin (eg. E-cadherin and N-cadherin), atypical cadherin, desmocollins, desmogleins, protocadherin type, and others. Cadherins act as Ca2+-dependent transmembrane glycoproteins that mediate cell-cell adhesion, which are involved in a variety of signaling including Wnt/β-catenin, PI3K/Akt, Rho GTPase, NF-κB, and other pathways.
Many studies suggested that abnormal expression of cadherin is associated with various diseases, such as asthma [4], chronic periodontitis [5], atherosclerosis [6], and diabetes [7] etc. On top of that, cell adhesion molecules also play key roles in tumor suppression and cell migration. For example, E-cadherin is considered as an important tumor suppressor gene. N-cadherin functions mainly as a promoter of tumors [8-10]. Therefore, Cadherins may be served as therapeutic targets to treat allergies, autoimmune diseases, and tumors.
Cadherin-17 (corresponding to CDH17), also called liver–intestine (LI) cadherin or human peptide transporter-1 (HPT-1), is a newly discovered unique member of the cadherin superfamily [11]. CDH17 was originally cloned from rat liver in 1994. The human CDH17 gene is located on chromosome 8q22.1, which encodes LI-cadherin protein. CDH17 has similarity to the classic cadherins but is structurally distinct: i) CDH17 consists of seven cadherin repeats within the extracellular domain, and classic cadherins have five; ii) AAL-sequence motif is found, instead of the HAV-motif in the cell adhesion recognition site of the extracellular cadherin-1 (EC-1); iii) CDH17 has only 20 amino acids in the cytoplasmic domain, whereas classic cadherins have a highly conserved cytoplasmic domain consisting of 150-160 amino acids (Figure 1) [12-14].
Figure 1. CDH17 structure [14]
CDH17 expression is highly restricted to epithelial cells in the small intestine and colon of both embryonic and adult mice and human. Notably, its expression is not detectable in the liver. CDH17 expression is known to be regulated by caudal-related homeobox transcription factor (CDX2) [12-14]. CDX2 has been reported as a tumor suppressive factor in colon cancer. It has been reported that CDH17 is a highly specific and more sensitive marker than CK20 and CDX2. In addition, CDH17 expression enhanced integrin activation and signaling, which is correlated with a moderately increased adhesion. Accumulated evidence has shown that CDH17 is overexpressed in many gastric cancer cells (GICs) [15-18].
CDH17 plays a crucial role in the cell adhesion process, similar to cadherin. β-catenin has essential roles in cell adhesion, but there is no direct association between CDH17 and β-catenin network [19-23]. CDH17 might perform its adhesion function by directly connecting to the cell scaffold. The precise biological function of CDH17 is still a matter of debate. To date, CDH17 has been identified in various tumors, including gastric, colorectal, hepatic, pancreatic and bile duct cancers. In a nutshell, CDH17 represents a previously unappreciated biomarker that might function as an independent adverse prognostic factor or therapeutic target for GIC patients [21-23].
Studies have revealed that the dysfunction of CDH17 is linked to the peripheral infiltration and metastasis of tumor cells, which has implications for tumor recurrence and patient survival. However, the mechanism of CDH17 in tumors has not been elucidated yet.
In gastric cancer, CDH17 overexpression dissociates the E-cadherin/catenin complex [23] that are involved in the cancer development via the Wnt signaling pathway [24-25]. In addition, CDH17 upregulation has influences on GSK3 activity, inhibiting the formation of β-catenin-AXIN-APC-GSK3 complex. Then increased β-catenin can bind to LEF/TCF, inducing Cyclin D1 expression, thus promoting cell proliferation and inhibiting apoptosis (Figure 2) [26]. It has been suggested that aberrant Galectin-3 in gastric cancer mediates CDH17 expression, but the exact regulatory mechanism needs to be further investigated [27-28].
Figure 2. CDH17 induces Cyclin D1 expression [26]
In addition, up-regulated CDH17 expression enhances the activity of MMP-2 and MMP-9, facilitating tumor cell metastasis [17]. Plus, CDH17 could be enhanced by Ras/Raf/MEK/ERK signaling pathway that plays an important role in the proliferation of gastric cancer cells (Figure 3) [29]. In hepatocellular carcinoma, down-regulated CDH17 expression leads to inactivation of the Wnt/β-catenin signaling pathway and inhibition of tumor growth. Thus, it is hypothesized that targeting CDH17 might promote apoptosis of tumor cells via blocking Wnt signaling pathway [30].
Figure 3. CDH17 mediates the Ras/Raf/MEK/ERK signaling pathway [29]
CDH17, as a novel cadherin, plays an important role in cell-cell adhesion and cell recognition. Dysregulation of intercellular adhesion and motility is one of the important mechanisms of tumor development. In recent years, there has been a growing focus on exploring the connection between CDH17 and tumors, particularly in gastrointestinal cancers like gastric, liver, colon, and pancreatic cancers.
CDH17 was first found to be overexpressed in gastric cancer. A clinical study from 71 gastric cancer patients revealed that CDH17 expression was positively correlated with the histological type, tumor invasion, and lymph node metastasis of gastric cancer. In the BGC-823 cell line, CDH17 overexpression promoted the proliferation, invasion, and migration of gastric adenocarcinoma. In MKN-45 gastric cancer cells, CDH17 downregulation curbed the proliferation, invasion, and adhesion of cells; NF-κB signaling pathway was inhibited and its downstream protein (VEGF-C and MMP-9) were reduced [31-33].
CDH17 is also related to liver cancer. The analysis of 57 cases by RT-PCR showed that CDH17 in liver cancer tissues was significantly higher than that in normal groups, indicating that CDH17 may be used as a tumor marker for early diagnosis of liver cancer [34]. A study of 34 cases of intrahepatic cholangiocarcinoma found that CDH17 was associated with the degree of tumor differentiation and vascular invasion. CDH17 knockdown promoted MTF-1 and PLGF expression, which in turn induced tumor angiogenesis [11, 35]. Another study found that splice isoforms and gene polymorphisms of CDH17 increase the risk of hepatocellular carcinogenesis [26].
A study of 45 colon cancer specimens found that down-regulation of CDH17 was significantly associated with colon cancer progression and lymph node metastasis. The consistent expression has been observed between CDH17 expression in colon cancer tissues at the primary site and metastatic sites. Therefore, CDH17 shows potential as a marker for detecting the metastasis of colon cancer [22, 36].
One study demonstrated a relationship between CDH17 immunoreactivity in esophageal adenocarcinoma and clinical characteristics of patients. The data found that there was a higher CDH17 immunoreactivity in well-differentiated esophageal cancer tissues, while the CDH17 was low or insignificant in low-differentiated esophageal adenocarcinoma tissues [37]. In esophageal squamous cell carcinoma ESCC, CDH17 CpG island methylation was enhanced and CDH17 was decreased [38-39]. Therefore, CDH17 could be a new target for esophageal cancer treatment.
In pancreatic cancer, CDH17 expression was higher in highly differentiated pancreatic ductal carcinoma than in those with poorly differentiated carcinomas. Kaplan-Meier analysis indicated that high CDH17 expression was associated with prognostic survival [40]. Low CDH17 expression was associated with tumor dedifferentiation. Additional research is required to fully understand the correlation between CDH17 and clinicopathological features of pancreatic cancer, as there are few of relevant studies.
CDH17 is also found in high levels in other types of cancer, like ovarian cancer and intraductal papillary mucinous neoplasm (IPMN). CDH17 is highly expressed in ovarian epithelial carcinoma, which was associated with poor prognosis [41]. CDH17 also plays a role in causing intestinal-type differentiation in IPMN [42]. Overall, CDH17 may be helpful in diagnosing and predicting the progression and recurrence of certain cancers such as gastric, hepatocellular, and colorectal cancers.
Several CDH17-based clinical agents are currently under development (Table 1), mainly for the treatment of gastrointestinal cancers. Among them, three are three bispecific antibodies: ARB-202 (CDH17 x CD3), ARB-001.T (CDH17 x CD3), BI-905711 (CDH17 x DR5/TRAIL-R2); one CAR-T drug CHM-2101; and two monoclonal antibodies. Surgery accompanied by chemotherapy and radiotherapy remains the first option for gastrointestinal tumors, but they aren't always very effective.
Tumor-targeted immunotherapy presents a promising new approach to treating cancer that is highly effective, safe, and low-toxic. This innovative strategy has the potential to revolutionize the current treatment landscape. Notably, recent research findings have demonstrated that inhibiting CDH17 can effectively impede tumor growth. As such, CDH17, as a newly discovered liver-intestine cadherin, is becoming a potential target for gastrointestinal tumors!
| Drugs | Target | Mechanism of action | Drug Type | Indications | Institutes | R&D status |
|---|---|---|---|---|---|---|
| ARB-202 | CDH17; CD3 |
Immunomodulators. CDH17 modulator; CD3 modulator |
Bispecific antibodies |
Bile duct cancer. Colorectal cancer. Gastrointestinal tumors; gastric cancer; biliary tract tumors; pancreatic cancer; liver cancer; pancreatic alveolar cancer |
Arbele | Clinical Phase 1 |
| BI-905711 | DR5; CDH17 |
DR5 agonist. CDH17 modulators |
Bispecific antibodies |
Diffuse large B-cell lymphoma. Gastric cancer. Bile duct cancer; gastrointestinal tract tumor; pancreatic cancer; esophageal cancer; bile duct cancer |
C.H. Boehringer Sohn AG & Co. KG; Boehringer Ingelheim (China) Investment Co. Boehringer Ingelheim (China) Investment Co. Boehringer Ingelheim GmbH |
Clinical Phase 1 |
| Anti-CDH17 mAbs (ProAlt) | CDH17 | CDH17 modulator | Monoclonal antibodies | Metastatic colorectal cancer; metastatic melanoma | Proclara Biosciences, Inc. | Preclinical |
| ARB-001. | CDH17 | CDH17 antagonist | Bispecific antibodies | Gastrointestinal tumors | Arbele | Preclinical |
| ARB-001. | CD3; CDH17 | CDH17 modulator | Bispecific antibodies |
Colorectal cancer; liver cancer. Stomach cancer |
Arbele | Preclinical |
| ARB-201 | CDH17 | CDH17 antagonist; CD3 inhibitor | Bispecific antibodies | Colorectal Cancer | Arbele | Preclinical |
| CHM-2101 | CDH17 | CDH17 regulator; gene transfer | CAR-T |
Colorectal cancer. Gastrointestinal tumors. Neuroendocrine tumors |
/ | Preclinical |
| CHM-2301 | CDH17 | CDH17 modulator | CAR-NK | Solid tumors | / | Preclinical |
| Anti-CDH17-based antibody drug conjugates (ProAlt) | CDH17 | CDH17 modulator | ADC; monoclonal antibody | Colorectal Cancer | Protein Alternatives SL | Drug Discovery |
Table 1: Clinical drugs in development for CDH17
To fully support researchers and pharmaceutical companies in their research on CDH17 in gastrointestinal cancers, CUSABIO presents CDH17 active protein (Code: CSB-MP613267HU) to support your research on the mechanism of CDH17 or its potential clinical value. (click for the full list of CDH17 products: CDH17 Protein; CDH17 antibody).
CDH17 Protein&Human CDH17 Stable Cell Line
CDH17 Antibody
References
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