# A Patient‐Derived Organoid Biobank of Adamantinomatous Craniopharyngioma as a Platform for Drug Discovery

## TL;DR

Researchers created a biobank of organoids from ACP tumors to study drug responses and found that Ceritinib may inhibit tumor growth.

## Contribution

A large-scale biobank of ACP patient-derived organoids with high success rate and drug screening capabilities is established.

## Key findings

- ACP patient-derived organoids accurately reflect the histology and genetics of original tumors.
- Ceritinib shows potent anti-tumor activity in ACP organoids by inhibiting a key signaling pathway.
- Clinical cases suggest caution in using Ceritinib due to initial tumor growth before therapeutic effects.

## Abstract

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.

This study successfully establishes adamantinomatous craniopharyngioma (ACP) patient‐derived organoids (PDOs) that preserve the histopathological and genetic features of the original tumors. Through drug sensitivity assays and subsequent mechanistic analyses, the study demonstrates that Ceritinib exerts its inhibitory effects on ACP PDO growth by downregulating the IGF‐1R/PI3K/AKT/GSK‐3β/β‐catenin axis. Concurrently, clinical case studies provide preliminary, hypothesis‐generating evidence suggesting that Ceritinib may have therapeutic potential against ACP.