{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Coy S"],"funding":["Ludwig Center at Harvard","National Brain Tumor Society","Pediatric Brain Tumor Foundation","NCI NIH HHS","National Institutes of Health","Accelerate Brain Cancer Cure","NIH HHS"],"pagination":["458-472"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10912007"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["26(3)"],"pubmed_abstract":["<h4>Background</h4>Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid and hematologic malignancies, including those expressing HER2, TROP2, and NECTIN4. Recently, an ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level expression of ADC targets may be sufficient for treatment responsiveness. However, ADC target expression is poorly characterized in many central nervous system (CNS) tumors.<h4>Methods</h4>We analyzed publicly available RNA-sequencing and proteomic data from the children's brain tumor network (N = 188 tumors) and gene-expression-omnibus RNA-expression datasets (N = 356) to evaluate expression of 14 potential ADC targets that are FDA-approved or under investigation in solid cancers. We also used immunohistochemistry to measure the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma, oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (N = 575).<h4>Results</h4>Pan-CNS analysis showed subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas strongly expressed HER2, while meningiomas showed weak-moderate HER2 expression. ACP and PCP strongly expressed B7-H3, with TROP2 expression in whorled ACP epithelium. AT/RT strongly expressed CLDN6. Glioblastoma showed little subtype-specific marker expression, suggesting a need for further target development.<h4>Conclusions</h4>CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be warranted."],"journal":["Neuro-oncology"],"pubmed_title":["Systematic characterization of antibody-drug conjugate targets in central nervous system tumors."],"pmcid":["PMC10912007"],"funding_grant_id":["U2C-CA233262","T32-CA009216","T32 CA009216","P30 CA006516","R01 CA194005","P41-EB028741","R01-CA188288","U54-CA210180","R01-CA194005","P30-CA06516","U2C CA233262","P01-CA163205"],"pubmed_authors":["Lee JS","Ligon KL","Santagata S","Sorger PK","Coy S","Woo T","Jones J","Chan SJ","Alexandrescu S","Wen PY"],"additional_accession":[]},"is_claimable":false,"name":"Systematic characterization of antibody-drug conjugate targets in central nervous system tumors.","description":"<h4>Background</h4>Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid and hematologic malignancies, including those expressing HER2, TROP2, and NECTIN4. Recently, an ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level expression of ADC targets may be sufficient for treatment responsiveness. However, ADC target expression is poorly characterized in many central nervous system (CNS) tumors.<h4>Methods</h4>We analyzed publicly available RNA-sequencing and proteomic data from the children's brain tumor network (N = 188 tumors) and gene-expression-omnibus RNA-expression datasets (N = 356) to evaluate expression of 14 potential ADC targets that are FDA-approved or under investigation in solid cancers. We also used immunohistochemistry to measure the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma, oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (N = 575).<h4>Results</h4>Pan-CNS analysis showed subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas strongly expressed HER2, while meningiomas showed weak-moderate HER2 expression. ACP and PCP strongly expressed B7-H3, with TROP2 expression in whorled ACP epithelium. AT/RT strongly expressed CLDN6. Glioblastoma showed little subtype-specific marker expression, suggesting a need for further target development.<h4>Conclusions</h4>CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be warranted.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2025-04-18T13:08:01.045Z","creation":"2025-04-06T22:40:02.396Z"},"accession":"S-EPMC10912007","cross_references":{"pubmed":["37870091"],"doi":["10.1093/neuonc/noad205"]}}