Patient-derived organoids predict personalized drug response and reveal alternative therapeutic options in glioblastoma.
Summary
This study established 18 patient-derived glioblastoma organoid (GBO) lines that faithfully preserve the histopathological and genomic features of parental tumors. Glioblastoma organoid-based drug sensitivity testing (GBO-DST) demonstrated a strong correlation with progression-free survival and proved superior to MGMT methylation status in predicting temozolomide response. Transcriptomic analysis elucidated mechanisms of temozolomide resistance, including mismatch repair deficiency and elevated MGMT expression. Furthermore, FDA-approved drug screening using GBO-DST identified regorafenib and lazertinib as effective therapeutic alternatives, with lazertinib showing superior efficacy in a GBO transplantation mouse model. These findings highlight the significant potential of GBO-DST as a robust platform for precision oncology in glioblastoma.
Analysis
CLINIQUE: This study presents a significant clinical advancement by proposing glioblastoma organoids (GBOs) as a predictive platform for therapeutic response. The GBO-based drug sensitivity testing (GBO-DST) demonstrated a strong correlation with patient progression-free survival and outperformed MGMT methylation status in predicting response to temozolomide, the only approved first-line therapy. The identification of regorafenib and lazertinib as effective therapeutic alternatives, with in vivo validation for lazertinib, paves the way for phase II/III clinical trials. These findings could justify clinical trials to evaluate these new therapies and potentially alter clinical practice by offering a precision medicine approach for glioblastoma, with a potential clinical impact in the medium term (3-5 years). BIOMOL: From a biomolecular perspective, the establishment of 18 GBO lines that preserve the histopathological and genomic features of parental tumors is a major advance for disease modeling. Transcriptomic analysis was instrumental in deciphering temozolomide resistance mechanisms, including mismatch repair deficiency, elevated MGMT expression, and upregulation of genes associated with axonogenesis and cell adhesion. GBO-DST represents a robust in vitro drug screening technology, enabling the identification of novel therapeutic options. This platform offers promising analytical validity for predicting drug response and could be integrated into clinical tests to guide personalized treatments.