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Abstract：
Advances in multiagent chemotherapy have led to recent improvements in survival for patients with acute lymphoblastic leukemia (ALL); however, a significant fraction do not respond to frontline chemotherapy or later relapse with recurrent disease, after which long-term survival rates remain low. To develop new, effective treatment options for these patients, we conducted a series of high-throughput combination drug screens to identify chemotherapies that synergize in a lineage-specific manner with MRX-2843, a small molecule dual MERTK and FLT3 kinase inhibitor currently in clinical testing for treatment of relapsed/refractory leukemias and solid tumors. Using experimental and computational approaches, we found that MRX-2843 synergized strongly-and in a ratio-dependent manner-with vincristine to inhibit both B-ALL and T-ALL cell line expansion. Based on these findings, we developed multiagent lipid nanoparticle formulations of these drugs that not only delivered defined drug ratios intracellularly in T-ALL, but also improved anti-leukemia activity following drug encapsulation. Synergistic and additive interactions were recapitulated in primary T-ALL patient samples treated with MRX-2843 and vincristine nanoparticle formulations, suggesting their clinical relevance. Moreover, the nanoparticle formulations reduced disease burden and prolonged survival in an orthotopic murine xenograft model of early thymic precursor T-ALL (ETP-ALL), with both agents contributing to therapeutic activity in a dose-dependent manner. In contrast, nanoparticles containing MRX-2843 alone were ineffective in this model. Thus, MRX-2843 increased the sensitivity of ETP-ALL cells to vincristine in vivo. In this context, the additive particles, containing a higher dose of MRX-2843, provided more effective disease control than the synergistic particles. In contrast, particles containing an even higher, antagonistic ratio of MRX-2843 and vincristine were less effective. Thus, both the drug dose and the ratio-dependent interaction between MRX-2843 and vincristine significantly impacted therapeutic activity in vivo. Together, these findings present a systematic approach to high-throughput combination drug screening and multiagent drug delivery that maximizes the therapeutic potential of combined MRX-2843 and vincristine in T-ALL and describe a novel translational agent that could be used to enhance therapeutic responses to vincristine in patients with T-ALL. This broadly generalizable approach could also be applied to develop other constitutively synergistic combination products for the treatment of cancer and other diseases.
摘要：
多药化疗的进展导致急性淋巴细胞白血病（ALL）患者生存率的近期改善；然而，很大一部分对一线化疗没有反应或后来复发，之后，长期生存率仍然很低。开发新的，这些患者的有效治疗选择，我们进行了一系列高通量联合药物筛选,以鉴定能够以谱系特异性方式与MRX-2843协同作用的化疗,MRX-2843是一种小分子MERTK和FLT3激酶双重抑制剂,目前正在临床试验中用于治疗复发性/难治性白血病和实体瘤.使用实验和计算方法，我们发现MRX-2843与长春新碱具有很强的协同作用,并以比率依赖性方式抑制B-ALL和T-ALL细胞系扩增.基于这些发现,我们开发了这些药物的多剂脂质纳米颗粒制剂，不仅在T-ALL细胞内递送确定的药物比例，而且在药物封装后也提高了抗白血病活性。在用MRX-2843和长春新碱纳米颗粒制剂治疗的原发性T-ALL患者样品中，提示其临床相关性。此外，在早期胸腺前体T-ALL（ETP-ALL）的原位鼠异种移植模型中，纳米颗粒制剂降低了疾病负担并延长了存活时间。两种药物都以剂量依赖的方式有助于治疗活性。相比之下,在该模型中，单独含有MRX-2843的纳米颗粒无效。因此，MRX-2843在体内增加了ETP-ALL细胞对长春新碱的敏感性。在这种情况下，添加剂颗粒，含有更高剂量的MRX-2843，提供比协同颗粒更有效的疾病控制。相比之下,含有更高的颗粒，MRX-2843和长春新碱的拮抗比效果较差。因此，药物剂量和MRX-2843与长春新碱之间的比例依赖性相互作用均显著影响体内治疗活性.一起,这些发现为高通量联合药物筛选和多药给药提供了一个系统的方法,该方法最大限度地发挥了MRX-2843和长春新碱在T-ALL中的联合治疗潜力,并描述了一种可用于增强T-ALL患者对长春新碱的治疗反应的新型翻译剂.这种可广泛推广的方法也可以应用于开发用于治疗癌症和其他疾病的其他组成型协同组合产品。
