Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer
| Autor: | Fara Brasó-Maristany, Laia Paré, D. Martinez, Francesco Schettini, S. De Placido, Patricia Galván, S. Guedan, Andreu Prat, P. Barbao |
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| Přispěvatelé: | Schettini, F, Barbao, P, Brasó-Maristany, F, Galván, P, Martínez, D, Paré, L, De Placido, S, Prat, A, Guedan, S |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
tumor surface antigen
Cancer Research Immunoconjugates T-Lymphocytes Cell Immunotherapy Adoptive Breast cancer intrinsic subtypes Original Research Receptors Chimeric Antigen biology Cell adhesion molecule GPI-Linked Protein CAR-T medicine.anatomical_structure Oncology Cèl·lules T tumor surface antigens Female Antibody Breast Neoplasm Human intrinsic subtype In silico Cellular therapy T cells Breast Neoplasms antibody–drug conjugates GPI-Linked Proteins Càncer de mama breast cancer Antigen Antigens CD medicine Humans differential gene expression Gene Teràpia cel·lular antibody–drug conjugate Fibroblast growth factor receptor 4 medicine.disease Expressió gènica T-Lymphocyte Immunoconjugate Cell Adhesion Molecule biology.protein Cancer research Gene expression Cell Adhesion Molecules |
| Zdroj: | ESMO Open |
| Popis: | Background Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody–drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation. Methods We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets. Results We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database. Conclusions Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC. Highlights • ADCs and CAR-T therapies target TSAs. • We propose a novel bioinformatic-based methodology to identify BC subtype-specific TSA for ADC and CAR-T. • As proof of concept we identified 36 potentially suitable and subtype-specific targets and predicted their toxicity profile. • We also identified 63 potential TSA pairs that might be appropriate for co-targeting. • The methodology was relatively easy to reproduce, less time- and resource-consuming and based on publicly available databases. |
| Databáze: | OpenAIRE |
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