TMOD-39. Modeling Vorasidenib response in IDH-Mutant gliomas with NanoGlio

Abstract Isocitrate dehydrogenase-mutant (IDHmut) gliomas are a distinct subset of diffuse gliomas in younger adults, including WHO Grade 2–3 oligodendrogliomas and astrocytomas, as well as a subset of Grade 4 astrocytomas. The recent INDIGO trial demonstrated the efficacy of Vorasidenib (Vora), a targeted mIDH inhibitor, in non-enhancing, treatment-naïve, low-grade (Grade II) IDHmut gliomas, leading to FDA approval in August 2024. However, nearly one-half of patients in the trial demonstrated progression at ~20 months and response rates in MRI contrast-enhancing and/or high-grade gliomas remain limited. This underscores the urgent need to (1) understand sensitivity and resistance mechanisms to Vora and (2) develop salvage therapies for a broader range of IDHmut glioma patients. A major obstacle is the scarcity of clinically relevant, patient-derived IDHmut models, particularly from low-grade gliomas. To address these limitations, we developed NanoGlio, a nanoliter-volume organoid platform, enabling rapid generation of patient-derived IDHmut glioma models and assessment of Vora sensitivity within 14-21 days. We established NanoGlio cultures from five Grade 2, one Grade 3, and four Grade 4 IDHmut cases—three with both enhancing and non-enhancing regions—as well as five IDH wild-type controls. Growth and morphology in NanoGlio varied by WHO grade: low-grade tumors grew slowly with lower cellularity, while high-grade IDHmut tumors proliferated rapidly. Vora induced morphological changes in low-grade and non-enhancing high-grade organoids but increased proliferation in enhancing high-grade organoids. Bulk RNA sequencing showed that NanoGlio recapitulates 15 of the top 20 pathways altered in clinical IDH inhibitor trials, with trends in gene expression changes closely mirroring those observed in patient samples. Vora treatment induced upregulation of neural function- and tumor suppression-associated genes, such as NPTX1, SPOCK2, SEZ6, NR1D1, OPCML and SNAP25, in IDHmut organoids. Future work will incorporate single-cell RNA sequencing to refine differentiation trajectories and uncover resistance mechanisms.