TMOD-21. Precision Oncology for High-Grade Gliomas: A Tumor Organoid Platform for Rapid, Patient-Specific Drug Screening

Abstract INTRODUCTION High-grade gliomas (HGGs) are aggressive, treatment-resistant brain tumors marked by extensive intratumoral heterogeneity, complicating formulation of effective adjuvant therapy. Standard of care treatment is unimodal and fails to eradicate the tumor in the majority of patients. Traditional models like spheroids and patient-derived xenografts (PDXs) offer biological insights but lack feasibility for clinical translation. Patient-derived glioma tumor organoids (GTOs), by contrast, are rapidly scalable, preserve native tumor architecture, and enable high-throughput patient-specific drug testing. OBJECTIVE To establish a reproducible, high-throughput GTO platform that faithfully models glioma biology and enables individualized therapeutic screening within a clinically actionable timeframe. METHODS Multi-regional tumor samples from IDH-wildtype, IDH-mutant, and H3K27M-mutant gliomas were collected during clinically-indicated tumor resection, minced, and cultured for 2–4 weeks in specialized medium. Organoids were characterized using multimodal microscopy and bulk RNA sequencing to assess fidelity to native tumor as well as inter-organoid heterogeneity in oncogenic drivers and glioma cell state. High-throughput drug screening was performed to evaluate intra- and inter-patient treatment response variability. RESULTS Histological analysis revealed heterogeneity in cellular architecture and cell state (OPC-like, MES-like, and AC-like) marker expression across organoids. RNA-sequencing confirmed preservation of transcriptional diversity in cell state proportions and highlighted differential activation of oncogenic pathways (WNT, MAPK, JAK-STAT). Drug screening revealed significant variability in therapeutic sensitivity across regions and patients, underscoring the importance of personalized treatment strategies and multi-drug regimens. CONCLUSIONS This study demonstrates feasibility of a rapid, scalable GTO platform for precision oncology in HGG, capable of informing patient-specific treatment selection. While limitations remain—including absence of immune microenvironment and delivery across the blood-brain barrier—GTOs represent a promising tool for nominating personalized multi-drug treatment regimens and for refining patient selection in clinical trials.