TMOD-07. Patient-derived glioblastoma organoids enable prediction of drug response and identification of therapeutic candidates in glioblastoma

Glioblastoma multiforme (GBM) remains a highly aggressive brain tumor with limited treatment options and poor prognosis. Temozolomide (TMZ) is the only approved first-line therapy, but frequent resistance limits its efficacy, highlighting the urgent need for alternative treatments. Between Aug 2021 and Sep 2023, 30 fresh GBM samples from 28 patients were transferred to the laboratory immediately after surgery, and glioblastoma organoids (GBOs) were cultured following an established protocol. We established 19 GBO lines, achieving a success rate of 63.3%, while preserving the histopathological and genomic features of parental tumors. Of these, 10 GBOs derived from tumors that had reached the clinical primary endpoint of progression were selected for TMZ sensitivity assessment using the GBO-based drug sensitivity testing (GBO-DST). Notably three GBO lines demonstrated less than 50% viability at 50 µM of TMZ, whereas other GBO lines did not achieve similar sensitivity. Progression-free survival (PFS) differed significantly according to TMZ sensitivity as determined by GBO-DST (p = 0.011). GBO-DST showed a strong correlation with PFS and outperformed O6-methylguanine-DNA methyltransferase (MGMT) methylation status in predicting TMZ responsiveness. Transcriptomic analysis identified mechanisms of TMZ resistance, including loss of mismatch repair, elevated MGMT expression, and upregulation of genes associated with axonogenesis and cell adhesion. To explore alternative therapeutic options, we screened FDA-approved drugs and identified lazertinib, a third-generation EGFR inhibitor, as a promising candidate for GBM. Lazertinib significantly reduced tumor size and cellular proliferation, even in TMZ-resistant GBOs. Its efficacy was further validated in vivo using patient-derived organoid xenograft models, which demonstrated a marked decrease in tumor mitotic activity. These findings underscore the potential of GBO-DST as a robust platform for personalized drug screening, advancing patient-specific GBM treatment strategies.