Repurposing FDA-Approved Drugs for Temozolomide-Resistant IDH1 Mutant Glioma Using High-Throughput Miniaturized...

Area of Science:

• Oncology
• Drug Discovery
• Genomics

Background:

• Recurrent gliomas with IDH1 mutations present significant treatment challenges due to drug resistance.
• Limited therapeutic options necessitate novel drug discovery and repurposing strategies.

Purpose of the Study:

• To identify FDA-approved drugs effective against recurrent IDH1-mutant gliomas using a high-throughput screening approach.
• To explore novel mechanisms of action and potential therapeutic targets for these challenging tumors.

Main Methods:

• A miniaturized, high-throughput screening of 2208 FDA-approved drugs was performed on patient-derived temozolomide-resistant IDH1-mutant glioma tumorspheres.
• Proteomics and pathway analyses were employed to identify drug targets and biomarkers.
• Publicly available genomic datasets were analyzed to correlate gene expression with patient survival.

Main Results:

• Over 20 drugs, including verteporfin (VP), demonstrated significant anti-glioma activity.
• Proteomics suggested the nuclear pore complex as a potential VP target, independent of YAP1.
• NUP107 was identified as a potential upstream regulator of VP response and a biomarker for decreased survival in IDH1-mutant astrocytoma.

Conclusions:

• Drug repurposing using 3D glioma models offers a cost-effective approach to identify new treatments.
• The nuclear pore complex represents a promising target for developing therapies against IDH1-mutant gliomas.
• Verteporfin and NUP107 warrant further investigation for clinical application in treating IDH1-mutant gliomas.