Work

Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors

Year: 2024

Type: article

Abstract: Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy. • Metabolic fingerprints of pediatric kidney tumors are preserved in tumoroids • De novo nucleotide synthesis is highly activated in MRT and AT/RT • Nucleotide synthesis inhibition is specifically cytotoxic in MRT and AT/RT • Nucleotide synthesis inhibition delays MRT growth in vivo Malignant rhabdoid tumor (MRT) is an aggressive childhood cancer with limited treatment options. Using patient-derived tumor organoids (tumoroids), Kes et al. identify nucleotide biosynthesis as a vulnerability in MRT. Treatment with methotrexate (MTX) and BAY-2402234 reduced nucleotide levels and induced apoptosis in vitro , with MTX demonstrating reduced MRT growth in vivo .

Source: Cell Reports Medicine

DOI: 10.1016/j.xcrm.2024.101878