TP53突变的Ewing肉瘤中的非化疗辅助剂。
Non-chemotherapy adjuvant agents in TP53 mutant Ewing sarcoma.
发表日期:2023 Sep 01
作者:
Jin-Ah Kim, Kenneth A Crawford, Piero A Spada, Leah R Martin, Jiaqi Zhang, Rain Wong, Joel M Reid, Clinton F Stewart, Timothy M Frank, Qianqian Liu, Joel E Michalek, Charles Keller
来源:
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要:
伊文肉瘤(EWS)是一种发生在骨骼或软组织中的恶性肿瘤,青少年和年轻成年患者以及后来的成年患者均有发病可能。尽管新诊断的非转移性EWS通常对治疗具有响应性,但复发病例存在无法满足的需求,目前尚无标准治疗方法。近期针对EWS的III期临床试验比较了7种与5种化疗药物,但未能改善生存率。为了延长EWS缓解的持久性,我们研究了3种非化疗辅助治疗药物候选药物与化疗联合使用。通过依赖锚定生长测定、基质无关腺瘤形成测定和EWS异种移植小鼠模型,我们调查了这些辅助药物的疗效。依诺沙星和恩替诺斯坦在长期体外和体内辅助研究中均表现出最佳效果。鉴于依诺沙星为FDA批准的抗生素,而恩替诺斯坦为尚未获得FDA批准的研究性药物,我们建议依诺沙星作为EWS患者进一步临床前和临床研究的辅助药物。© 2023. Springer Nature Limited.
Ewing sarcoma (EWS) is a malignant tumor arising in bone or soft tissue that occurs in adolescent and young adult patients as well as adults later in life. Although non-metastatic EWS is typically responsive to treatment when newly diagnosed, relapsed cases have an unmet need for which no standard treatment approach exists. Recent phase III clinical trials for EWS comparing 7 vs 5 chemotherapy drugs have failed to improve survival. To extend the durability of remission for EWS, we investigated 3 non-chemotherapy adjuvant therapy drug candidates to be combined with chemotherapy. The efficacy of these adjuvant drugs was investigated via anchorage-dependent growth assays, anchorage-independent soft-agar colony formation assays and EWS xenograft mouse models. Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.© 2023. Springer Nature Limited.