Spatial dissection of ADC/RPT targets defines therapeutic opportunities inrhabdoid tumors

Reitsam, N. G.; Fincke, V. E.; Hernandez Ramirez, M. D.; Mucha, M.; Sipos, E.; Siebenhueter, L.; Enke, J. S.; Lossner, M.; Vokuhl, C.; Hasselblatt, M.; Fruehwald, M.; Maerkl, B.; Johann, P. D.

doi:10.64898/2025.12.11.692900

bioRxiv · 10.64898/2025.12.11.692900

Spatial dissection of ADC/RPT targets defines therapeutic opportunities inrhabdoid tumors

Reitsam, N. G.·Fincke, V. E.·Hernandez Ramirez, M. D.·Mucha, M.·Sipos, E.·Siebenhueter, L.·Enke, J. S.·Lossner, M.·Vokuhl, C.·Hasselblatt, M.·Fruehwald, M.·Maerkl, B.·Johann, P. D.

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Abstract

Rhabdoid tumors (RT) are among the most aggressive pediatric malignancies, characterized by early onset, 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. 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, CXCR4, and IL13RA2 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). 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. 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 discovery in pediatric cancer.

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Reitsam, N. G., Fincke, V. E., Hernandez Ramirez, M. D., Mucha, M., Sipos, E., Siebenhueter, L., Enke, J. S., Lossner, M., Vokuhl, C., Hasselblatt, M., Fruehwald, M., Maerkl, B., Johann, P. D.. 2025-12-13. Spatial dissection of ADC/RPT targets defines therapeutic opportunities inrhabdoid tumors. https://doi.org/10.64898/2025.12.11.692900

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