Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
BMC Cancer. 2023 Apr 5;23(1):310. doi: 10.1186/s12885-022-10319-7.
Pediatric cancer is the leading cause of disease-related death in children and the need for better therapeutic options remains urgent. Due to the limited number of patients, target and drug development for pediatrics is often supplemented by data from studies focused on adult cancers. Recent evidence shows that pediatric cancers possess different vulnerabilities that should be explored independently from adult cancers.
Using the publicly available Genomics of Drug Sensitivity in Cancer database, we explore therapeutic targets and biomarkers specific to the pediatric solid malignancies Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. Results are validated using cell viability assays and high-throughput drug screens are used to identify synergistic combinations.
Using published drug screening data, PARP is identified as a drug target of interest across multiple different pediatric malignancies. We validate these findings, and we show that efficacy can be improved when combined with conventional chemotherapeutics, namely topoisomerase inhibitors. Additionally, using gene set enrichment analysis, we identify ribosome biogenesis as a potential biomarker for PARP inhibition in pediatric cancer cell lines.
Collectively, our results provide evidence to support the further development of PARP inhibition and the combination with TOP1 inhibition as a therapeutic approach in solid pediatric malignancies. Additionally, we propose ribosome biogenesis as a component to PARP inhibitor sensitivity that should be further investigated to help maximize the potential utility of PARP inhibition and combinations across pediatric solid malignancies.
儿科癌症是导致儿童死亡的主要原因，因此仍然迫切需要更好的治疗选择。由于患者人数有限，儿科的靶向治疗和药物开发通常需要补充针对成人癌症的研究数据。最近的证据表明，儿科癌症具有不同的脆弱性，这些脆弱性应该独立于成人癌症进行探索。
我们使用公开的癌症药物敏感性基因组学数据库，探索小儿实体恶性肿瘤尤文肉瘤、髓母细胞瘤、神经母细胞瘤、骨肉瘤和横纹肌肉瘤特有的治疗靶点和生物标志物。使用细胞活力测定法验证结果，并使用高通量药物筛选来鉴定协同组合。
使用已发表的药物筛选数据，我们确定 PARP 是多种不同小儿恶性肿瘤的潜在药物靶点。我们验证了这些发现，并表明当与常规化疗药物（即拓扑异构酶抑制剂）联合使用时，疗效可以提高。此外，通过基因集富集分析，我们发现核糖体生物发生是儿科癌细胞系中 PARP 抑制的潜在生物标志物。
总之，我们的结果为进一步开发 PARP 抑制以及将其与 TOP1 抑制联合作为小儿实体恶性肿瘤的治疗方法提供了证据。此外，我们提出核糖体生物发生是 PARP 抑制剂敏感性的一个组成部分，应该进一步研究以帮助最大限度地发挥 PARP 抑制剂和组合在小儿实体恶性肿瘤中的潜力。
