Spatial dissection of ADC/RPT targets defines heterogeneous expression landscapes and therapeutic implications in rhabdoid tumors

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ID: 315681
2026
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Abstract
BACKGROUND: Rhabdoid tumors (RT) are among the most aggressive pediatric malignancies, characterized by early onset in life, loss of SWI/SNF complex members (SMARCB1 or SMARCA4), and dismal outcomes despite multimodal therapy. Refractory and relapsing RT remain almost uniformly fatal, and targeted or immune-based approaches have yet to demonstrate clinical benefit. METHODS: To explore novel therapeutic vulnerabilities, we systematically investigated the expression of clinically actionable surface proteins that could serve as targets for antibody-drug conjugates (ADCs), radiopharmaceutical therapy (RPT), or cellular immunotherapies. Based on large-scale transcriptomic analyses, we prioritized FAP (fibroblast activation protein), CXCR4 (chemokine receptor 4), and IL13RA2 (interleukin receptor 13 RA2) and performed comprehensive protein-level validation by immunohistochemistry in an unprecedented cohort of 60 rhabdoid tumors spanning all molecular subgroups (ATRT-TYR, ATRT-SHH, ATRT-MYC and eMRT). RESULTS: Integrating these data with spatial and single-nucleus transcriptomic profiling, we identified subgroup- and cell-type-specific expression patterns, including heterogeneous FAP distribution between stromal and tumor compartments and a distinct IL13RA2-positive rhabdoid cell population with melanosomal and stem-like features: Overall 51/60 tumors demonstrated positivity, defined as immunohistochemical H-score above or at least equal to 10, for FAP in the stroma and 34/60 tumors for CXCR4, indicating that a substantial fraction of rhabdoid tumors may be amenable to targeted therapies directed against these epitopes. CONCLUSION: These findings define a set of biologically and clinically relevant surface targets in RT and provide a translational blueprint for rational ADC and RPT target development in pediatric cancer.
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openalex_W7163417206 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Nic G. Reitsam, Victoria E. Fincke, M.J. Martínez-Ramírez, Marlena Mucha, Éva Sipos, Siebenhüter Lisa, Johanna S. Enke, Maurice Loßner, Christian Vokuhl, Constantin Lapa, Martin Hasselblatt, Michael Frühwald, Bruno Märkl, Pascal D Johann
Journal journal of neuro-oncology
Year 2026
DOI
10.1093/neuonc/noag133
URL
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