TMOD-43. Development of Clinically Relevant Patient-Derived Brain Tumor Models for Advancing Therapeutic Evaluation

Abstract BACKGROUND Pediatric and adult brain tumors, including glioblastoma, astrocytoma, ependymoma, and medulloblastoma, are associated with poor prognosis and limited treatment options. Standard of care (SOC) therapies such as surgery, radiation, and chemotherapy often fail to control tumor progression and are associated with severe toxicity. The lack of personalized therapeutic approaches underscores the urgent need for clinically relevant human models that reflect tumor heterogeneity and enable testing of novel therapies, including immunotherapies. METHODS We analyzed a panel of ten low-passage patient-derived brain tumor (PBT) lines and matched patient-derived xenograft (PDX) models from surgical specimens. Tumors were characterized using single-cell and bulk RNA sequencing, DNA exome analysis, multiparameter flow cytometry, and immunohistochemistry. Freshly dispersed tumor (FDT) samples and derived PBT lines were compared to assess fidelity in maintaining key molecular and cellular features. RESULTS FDT-matched PBT lines were successfully established in approximately 70% of cases and preserved patient-specific mutations (IDH1, MGMT, p53, PTEN) and expression profiles of key therapeutic targets including IL13Rα2, EGFR, HER2, WNT1, JAK1/2, and NOTCH1-4. Correlation analysis demonstrated significant similarity between FDT and PBT profiles (R = 0.31, p = 0.018). Notably, PBTs and PDX models retained heterogeneous and non-clonal populations, enabling the identification of therapy-resistant subclones under in vitro selection pressures. These features support their use in evaluating used for the optimization of immunotherapy and other therapies for patients with brain tumors. CONCLUSION We report the generation of clinically relevant PBT and PDX models that recapitulate the molecular and histopathological features of primary brain tumors. These models provide a powerful platform for dissecting therapeutic response and resistance, and for advancing precision medicine approaches. Our work lays the foundation for optimizing immunotherapy and next-generation treatments for both pediatric and adult brain tumor patients.