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Published on: September 30, 2021
Profiling ADC targets in cholangiocarcinoma: implications for therapeutic development
Mari Nakazawa1, Waqar Arif2, Ezra Baraban2
1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mnakaza2@jh.edu.
Abstract:
Antibody drug conjugates (ADCs) are clinically active in several cancers, but their relevance in cholangiocarcinoma (CCA) is undefined. We profiled 23 CCA tumors and found that TROP2 was highly expressed (82.6%) but also present in benign epithelium. NECTIN4 (65.2%) showed tumor-specific staining, supporting selectivity. B7-H3 (47.8%) and CLDN18.2 (13.0%) were less frequently positive. IDH1-mutant tumors demonstrated attenuated ADC target expression. These data provide rationale for evaluating ADC strategies in CCA.
Insights
Antibody drug conjugates (ADCs) show promise for cholangiocarcinoma (CCA) treatment. NECTIN4 expression is tumor-specific, making it a potential ADC target in CCA, while TROP2 is also highly expressed.
Area of Science:
- Oncology
- Cancer Research
- Drug Development
Background:
- Antibody drug conjugates (ADCs) are effective in various cancers.
- The potential of ADCs in cholangiocarcinoma (CCA) remains unexplored.
- Identifying suitable molecular targets is crucial for ADC therapy in CCA.
Purpose of the Study:
- To investigate the expression of potential ADC targets in cholangiocarcinoma (CCA) tumors.
- To evaluate the suitability of TROP2, NECTIN4, B7-H3, and CLDN18.2 as targets for ADC therapy in CCA.
- To assess the impact of IDH1 mutations on ADC target expression in CCA.
Main Methods:
- Profiling of 23 cholangiocarcinoma (CCA) tumor samples.
- Immunohistochemical analysis to determine the expression levels and localization of TROP2, NECTIN4, B7-H3, and CLDN18.2.
- Correlation analysis between target expression and IDH1 mutation status.
Main Results:
- High expression of TROP2 (82.6%) was observed, but also in benign epithelium.
- NECTIN4 showed tumor-specific staining in 65.2% of cases, indicating high selectivity.
- B7-H3 (47.8%) and CLDN18.2 (13.0%) were less frequently expressed. IDH1-mutant tumors had lower expression of these ADC targets.
Conclusions:
- NECTIN4 is a promising tumor-specific target for antibody drug conjugate (ADC) therapy in cholangiocarcinoma (CCA).
- While TROP2 is highly expressed, its presence in benign tissues may limit selectivity.
- ADC strategies warrant further investigation in CCA, particularly targeting NECTIN4, considering the impact of IDH1 mutations on target expression.
