Background: Antibody-drug conjugates (ADCs) are an emerging therapeutic modality that enable targeted delivery of cytotoxic chemotherapy to tumor cells, thereby improving antitumor specificity while minimizing systemic toxicity.Here, we investigate the expression and landscape of ADC targets in gliomas. Methods:A comprehensive search for ADC targets was performed using Clinical-Trials.gov.Bulk transcriptomic data were obtained from TCGA-GBM (n=391) and TCGA-LGG (n=534), with normal brain samples from GTEx (n=400).Single-cell RNAseq data (GSE131928) were retrieved from TISCH2.0.Differential expression analysis (DEA) was conducted for GBM vs normal and LGG vs normal tissues.DEA of the single-cell dataset identified malignant cell marker genes, and bulk tumor-upregulated targets were filtered against these markers to identify malignant-specific ADC candidates.Correlation analyses were then performed using literature-validated sensitivity and resistance markers for ADC payloads, including topoisomerase inhibitors, maytansinoids, and auristatin derivatives.Finally, malignant-expressed ADC targets were evaluated for associations with patient survival.Results: A total of 60 ADC targets were retrieved, out of these targets 23 were significantly upregulated in both GBM and LGG (log2FC>0.5,p<0.05).Single-cell DEA identified 8 (DLL3, EGFR, CD38, FN1, SLC39A6, FOLR1, and CDH6) malignant cell cluster-upregulated targets.MUC1, FOLR1, and FN1 were significantly positively correlated with ADC sensitivity markers, including CTSB, CTSL, CTSA, and CTSC, which are lysosomal proteases that facilitate intracellular payload release.The other ADC targets showed significant negative correlation with most sensitivity markers.EGFR showed significant positive correlation to ABCB1 and ABCG2 resistance marker, known to confer resistance to auristatin and camptothecin payloads.Elevated expression of MUC1, FOLR1, and FN1 were significantly associated with worse survival outcomes in both LGG and GBM (p<0.05).Conclusions: MUC1, FOLR1, and FN1 emerge as key ADC targets in gliomas, showing malignant-specific expression, strong association with ADC payload sensitivity markers, and links to poor survival, supporting their therapeutic potential.
Schultz et al. (Sun,) studied this question.