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Anti-tumor effect of antibody-drug conjugate targeting cell adhesion molecule 1 on GIST cells representing small
Makoto Yoshida1, Jiayin Yuan2, Takako Kihara1
1Department of Surgical Pathology, Hyogo Medical University School of Medicine, Nishinomiya, Hyogo, Japan.
Abstract:
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.
Insights
An antibody-drug conjugate targeting cell adhesion molecule 1 (CADM1) demonstrated significant anti-tumor effects against CADM1-expressing gastrointestinal stromal tumor (GIST) cells in vitro and in vivo mouse models, offering a potential new treatment avenue.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the alimentary tract.
- Small intestinal GISTs have a worse prognosis than gastric GISTs.
- Acquired resistance to current tyrosine kinase inhibitors necessitates novel therapeutic strategies.
Purpose of the Study:
- To investigate the anti-tumor efficacy of an antibody-drug conjugate (ADC) targeting cell adhesion molecule 1 (CADM1) in human GIST cells.
- To evaluate the potential of anti-CADM1 ADC as a targeted therapy for CADM1-expressing GISTs.
Main Methods:
- Utilized GIST-T1 cell line (gastric origin, low CADM1 expression) and GIST-T1-CAD cells (engineered to highly express CADM1, mimicking small intestinal GIST).
- Assessed in vitro cytotoxicity of anti-CADM1 ADC and control ADC against GIST cell lines.
- Evaluated in vivo anti-tumor effects of anti-CADM1 ADC in subcutaneous and intraperitoneal mouse models (nude and SCID mice).
Main Results:
- Anti-CADM1 ADC exhibited significant cytotoxic activity against GIST-T1-CAD cells in vitro, while control ADC did not.
- Intravenous administration of anti-CADM1 ADC inhibited tumor growth in mice bearing GIST-T1-CAD xenografts.
- Intraperitoneal administration of anti-CADM1 ADC reduced peritoneal tumor burden in SCID mice.
- No apparent tissue or organ damage was observed in mice treated with anti-CADM1 ADC.
Conclusions:
- The anti-CADM1 ADC demonstrates potent anti-tumor activity against CADM1-expressing GIST cells.
- This ADC represents a promising therapeutic candidate for GIST, particularly for tumors expressing CADM1.
- Further investigation into anti-CADM1 ADC for GIST treatment is warranted.
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