Krieg K, Materna-Reichelt S, Naber T, Rachad FZ, Kauven P, Weller A, Haferkamp U, Wittich A, Zaliani A, Woo MS, Walkenhorst M, Siegmund M, Harberts J, Zierold R, Blick R, Conze C, Muschong P, Miltner D, Friese MA, Mezler M, Siegmund H, Evert K, Krasemann S, Gužvić NS, Klein CA, Werner-Klein M, Wegener J, Pless O.
Effective systemic therapies against brain metastases are severely limited. To understand and target vulnerabilities of human metastases in a brain niche context, we developed reproducible melanoma brain metastasis (MBM) models for metastasis-integrating drug screening. We co-cultured A375 melanoma cells or tumor regional lymph node-derived disseminated cancer cells (DCCs) in close proximity with human induced pluripotent stem cell-derived cortical organoids (hCOs). In these, RNA sequencing revealed an upregulation of metastasis-associated features. First, A375 cells and DCCs were screened against an anti-cancer library containing 315 compounds. Hits were ranked by neurotoxicity, central nervous system permeation, and anti-DCC efficacy. Only a minority of hits effectively targeted A375-MBMs, with the first-in-class XPO1 inhibitor selinexor emerging as top hit. Selinexor also demonstrated efficacy in DCC-MBM models and low toxicity on hCOs, suggesting a promising therapeutic window in clinically applied doses. Collectively, the MBM model provides a tool for identifying candidate therapies counteracting metastatic progression.Cell Rep Methods. 2025 Nov 14:101236
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