Kes Marjolein M G, Morales-Rodriguez Francisco, Zaal Esther A, de Souza Terezinha, Proost Natalie, van de Ven Marieke, van den Heuvel-Eibrink Marry M, Jansen Jeroen W A, Berkers Celia R, Drost Jarno
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
Cell Rep Med. 2025 Jan 21;6(1):101878. doi: 10.1016/j.xcrm.2024.101878. Epub 2024 Dec 20.
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.
恶性横纹肌样肿瘤（MRT）是最具侵袭性的儿童癌症之一，目前尚无有效的治疗方案。细胞代谢重编程是癌症的一个重要特征，多种基于代谢的药物已被批准用于癌症治疗。在本研究中，我们使用患者来源的肿瘤类器官（肿瘤oids）来描绘几种儿童癌症的代谢图谱。结合基因表达分析和质谱代谢物谱分析，我们发现核苷酸生物合成是MRT的一个特别脆弱点。用从头核苷酸合成抑制剂甲氨蝶呤（MTX）和BAY-2402234处理MRT肿瘤oids可降低MRT肿瘤oids中的核苷酸水平并诱导细胞凋亡。最后，我们在MRT患者来源的异种移植（PDX）小鼠模型中证明了MTX的体内疗效。我们的研究揭示了核苷酸生物合成是MRT特有的代谢脆弱点，这最终可能为患有这种致命儿童恶性肿瘤的儿童带来更好的治疗选择。
