Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma.
Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma.
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DOI：
10.1038/srep16991
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发表时间：
2015-11-25
影响因子：
4.6
通讯作者：
Reed DR
中科院分区：
文献类型：
--
作者：
Yu D;Kahen E;Cubitt CL;McGuire J;Kreahling J;Lee J;Altiok S;Lynch CC;Sullivan DM;Reed DR
全身治疗提高了骨肉瘤的无事件生存率和总生存率，但最初诊断的患者中有30-50%会出现疾病进展或复发，难以治愈。骨肉瘤具有复杂的核型，在绝大多数病例中缺失p53，并且缺乏复发性靶向通路。在这项研究中，我们探索了54种临床批准用于其他肿瘤适应症的药物，积极的临床开发中的药物，以及其他在5种骨肉瘤细胞系中具有临床可达到浓度的骨肉瘤临床前数据的药物。我们发现了多种药物的显著单药活性，并在两种药物组合的所有排列中测试了10种药物，以通过Chou和Talalay分析来定义协同组合。然后，我们评估了添加顺序，以选择最适合临床应用的组合。我们的结论是，骨肉瘤的化疗药物的再利用，通过使用体外系统可能会定义新的药物组合具有显着的体内活性。特别是，蛋白酶体抑制剂与组蛋白脱乙酰酶抑制剂和伊沙匹隆和MK 1775的组合在我们的测定中表现出优异的活性。
Systemic therapy has improved osteosarcoma event-free and overall survival, but 30–50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays.