Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer

Area of Science:

• Oncology
• Genomics
• Drug Discovery

Background:

• Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, lethal gynecologic malignancy affecting young patients.
• Current treatment options for SCCOHT are limited, and effective disease models for research are scarce.

Purpose of the Study:

• To establish reliable patient-derived models for SCCOHT.
• To identify potential therapeutic agents for SCCOHT using organoid drug profiling.

Main Methods:

• Eight patient-derived tumoroid lines were established from SCCOHT patient tumors.
• Organoid drug screening was performed using a library of 153 clinical compounds.
• RNA sequencing was used to investigate the mechanism of action of identified drugs.

Main Results:

• The established tumoroids accurately reflect the genomic and transcriptomic profiles of the original tumors, including intrapatient heterogeneity.
• Methotrexate demonstrated significant efficacy against SCCOHTs, with a clinically relevant IC50 of 35 nM.
• Methotrexate treatment induced TP53 pathway activation and apoptosis in SCCOHT cells.

Conclusions:

• Patient-derived tumoroids are valuable tools for modeling rare cancers like SCCOHT.
• Methotrexate is a promising therapeutic candidate for SCCOHT, warranting further clinical investigation.
• Organoid technology can accelerate the development of targeted therapies for rare malignancies.