Stewart Elizabeth, Goshorn Ross, Bradley Cori, Griffiths Lyra M, Benavente Claudia, Twarog Nathaniel R, Miller Gregory M, Caufield William, Freeman Burgess B, Bahrami Armita, Pappo Alberto, Wu Jianrong, Loh Amos, Karlström Åsa, Calabrese Chris, Gordon Brittney, Tsurkan Lyudmila, Hatfield M Jason, Potter Philip M, Snyder Scott E, Thiagarajan Suresh, Shirinifard Abbas, Sablauer Andras, Shelat Anang A, Dyer Michael A
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell Rep. 2014 Nov 6;9(3):829-41. doi: 10.1016/j.celrep.2014.09.028. Epub 2014 Oct 23.
Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNA-damaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using three different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice.
尤因肉瘤（EWS）是一种主要影响青少年和年轻成年人的骨与软组织肿瘤。采用目前的治疗方法，70%的局限性疾病患者能够存活，但转移性或复发性疾病患者的预后较差。我们发现EWS细胞系在DNA断裂修复方面存在缺陷，并且对聚（ADP-核糖）聚合酶抑制剂（PARPis）敏感。在给予DNA损伤剂伊立替康或替莫唑胺后，PARPi在EWS细胞中诱导的细胞毒性高10至1000倍。我们建立了一种原位EWS小鼠模型，并使用三种正在进行儿科癌症临床开发的不同PARPis进行了药代动力学和药效学研究。按照先前为儿科患者优化的低剂量、延长给药方案给予伊立替康，与PARPis联合使用时是一种有效的DNA损伤剂；与替莫唑胺联合使用相比，其耐受性也更好。PARPis与伊立替康和替莫唑胺联合使用在超过80%的小鼠中产生了完全且持久的反应。
