IDH1 Mutation Increases the Sensitivity of Glioma Organoids to Radiotherapy and Targeted Therapy

In gliomas, the Isocitrate Dehydrogenase (IDH1) mutation is a key molecular marker that can distinguish subtypes. IDH1-mutant gliomas grow more slowly, are sensitive to radiotherapy and chemotherapy, and have a better prognosis. However, there are still individual differences in treatment responses and prognosis among patients with this subtype, making traditional treatments difficult to adapt. Organoid models can simulate the characteristics of IDH1-mutant tumors and provide important support for research on their personalized treatment.

Glioma tissues were dissociated, and cells were resuspended in Matrigel before being seeded into culture dishes for IDH1-mutant organoid culture. Organoids at different culture stages were subjected to morphological observation and viability confirmation via live-dead staining. The growth curves of two-dimensional (2D) and three-dimensional (3D) cells were measured by adding CellTiter-Glo (CTG). Hematoxylin and Eosin (H&E) staining and immunohistochemistry were performed on cultured organoids and original tumor tissue sections to validate organoid phenotypes, while immunofluorescence assays confirmed the IDH1 mutation status. Drug sensitivity tests were conducted using temozolomide and vorasidenib on IDH1-mutant and IDHwildtype glioma organoids. Relative luminescence Units (RLU) were measured via CTG at various time points. Organoids were irradiated with 8 Gy γ-rays at day 0 and day 4, and cell viability was measured.

Immunohistochemical (IHC) results of the constructed organoids were consistent with those of the original tumor tissues, and immunofluorescence confirmed the presence of IDH1 mutations in the organoids. No significant difference in sensitivity to temozolomide was observed between IDH1-mutant and wild-type organoids, whereas IDH1-mutant organoids showed significantly higher sensitivity to vorasidenib than IDH-wildtype organoids. After 4 days of γ-ray irradiation, the cell viability of IDH1-mutant glioma organoids decreased significantly, while no significant change was observed in IDH-wildtype organoids.

This study generated patient-derived IDH1-mutant glioma organoids, validated their value as an individualized precision drug-testing platform by comparing drug sensitivity and radiotherapy responses with IDH-wildtype organoids, and found that IDH1-mutant organoids were more sensitive to radiotherapy and vorasidenib, advancing glioma precision treatment.

By constructing an IDH1-mutated glioma organoid model and integrating accurate molecular diagnostic information, it is expected to improve treatment efficacy and promote the development of personalized glioma medicine.