A Patient-Derived Organoid Biobank of Adamantinomatous Craniopharyngioma as a Platform for Drug Discovery.

Adamantinomatous craniopharyngioma (ACP), a benign yet clinically challenging neoplasm situated in sellar-suprasellar region, frequently causes hypothalamic dysfunction. Despite the identification of molecular alterations in ACP, the absence of robust research models has impeded the advancement of targeted therapies. Herein, the development of a large-scale ACP biobank comprising 54 patient-derived organoids (PDOs) is presented, achieves with a notable 90% success rate. Comprehensive characterization using hematoxylin and eosin (H&E) staining, immunofluorescence staining, and whole-exome sequencing (WES) demonstrates that PDOs faithfully recapitulate key histoarchitectural features, molecular marker expression profiles, and somatic mutational landscapes of corresponding parental tumors. Drug sensitivity screening reveals diverse responses of PDOs to the drugs tested, with Ceritinib exhibiting potent and consistent anti-tumor activity across seventeen PDOs evaluated. Further mechanistic investigations utilizing RNA transcriptomic sequencing have elucidated that Ceritinib inhibits PDO growth by downregulating the IGF-1R/PI3K/AKT/GSK-3β/β-catenin signaling axis. Additionally, a retrospective analysis of two Ceritinib-treated clinical cases reveals tumor growth with treatment before any possible therapeutic effects are observed, highlighting the need for caution and careful monitoring in treating ACP patients. Collectively, these findings demonstrate that ACP PDOs effectively preserve the biological characteristics of original tumors, thereby providing a valuable platform for developing precision therapies for ACP patients.