Precision oncology in a dish: patient-derived glioma organoids to guide novel therapeutic strategies

Gliomas are the most common primary brain tumors in adults and encompass a spectrum from IDH-mutant gliomas to highly aggressive IDH-wild type glioblastomas (GBM). Despite advances in our understanding of glioma biology, GBM remains largely incurable, with a median overall survival (mOS) of approximately 15 months and minimal improvements over recent decades. The current standard of care, maximal surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy, has proven insufficient, and experimental approaches such as immune checkpoint inhibitors and CAR-T cell therapies have also failed to provide meaningful survival benefits. These limitations highlight the urgent need for innovative, patient-specific platforms to evaluate novel therapeutic strategies. In this study, we established patient-derived glioma organoids (GOs) from 61 patients, including both IDH-mutant gliomas (GOmut) and IDH-wild type glioblastoma (GOwt). These organoids were characterized by a variety of techniques against their parental tumors. Afterwards, we performed in silico drug discovery with paired RNA-seq data and validated the results with diverse glioma models. GOs recapitulated the cellular heterogeneity, histological architecture, and molecular signatures of their parental tumors, including the preservation of clinically relevant features such as immune profiles, vascular structures, and tumor subtype. Notably, GOmuts retained the IDH mutation over extended culture periods. Importantly, GOs maintained resistance to standard chemotherapeutic agents, mirroring the limited response of gliomas to conventional chemotherapy. Our unbiased in silico screening via the DiSCoVER platform applied to RNA-seq data from paired tumors and GOs identified alectinib, dabrafenib, and ruxolitinib as promising candidates. All three compounds proved effective in in vitro cytotoxicity assays, with alectinib and ruxolitinib displaying significant antitumoral effects in vitro. Our findings establish GOs as a clinically relevant and biologically faithful platform for therapeutic screening in glioma. By integrating transcriptomics-based drug discovery with a patient-specific organoid model, we present an easy to implement platform for more effective and personalized treatments for glioma patients. Our findings also support the inclusion of two compounds, alectinib and ruxolitinib, in future clinical investigations.