Background/Objectives: Infants withKMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have high rates of relapse and poor survival compared with children. Few new therapies have been identified over the past twenty years. The aim of this study was to identify existing anti-cancer agents that have the potential to be repurposed for the treatment of infant ALL.Methods: Eight extensively characterized infant ALL cell lines were treated with 62 anti-neoplastic drugs in vitro to identify agents that exhibit significant cytotoxicity. From this screen, we selected the most effective and clinically translatable agent for further in vitro and in vivo assessment to determine the potential for use in the clinical setting.Results: Our anti-cancer drug screen revealed significant activity of dactinomycin across all infant ALL cell lines. Further in vitro testing identified low half-maximal inhibitory concentrations (IC50) across our infant ALL cell lines in the nanomolar range. Combination testing with the conventional chemotherapeutic agents currently used to treat infants with ALL demonstrated additivity with cytarabine. In vivo assessment of dactinomycin identified 36 μg/kg as the maximum tolerated dose, with unacceptable toxicities at higher dose treatment. Treatment using doses of 18 μg/kg administered either once or twice a week derived a small but significant survival benefit in patient-derived xenografts.Conclusions: Dactinomycin is extensively used for the treatment of solid tumors in children and has an acceptable safety profile when used to treat infants in this context. However, despite being readily translational and exhibiting promising in vitro cytotoxicity, dactinomycin showed limited efficacy in vivo and therefore does not represent a priority candidate for integrating into therapy for infants with ALL.
背景/目的：与儿童相比，KMT2A重排B细胞急性淋巴细胞白血病（ALL）婴儿患者的复发率高且生存率低。过去二十年来，鲜有新疗法被发现。本研究旨在筛选现有抗癌药物，探索其重新用于治疗婴儿ALL的潜力。 方法：对八种经过充分表征的婴儿ALL细胞系进行体外62种抗肿瘤药物处理，以筛选具有显著细胞毒性的药物。通过此筛选，我们选取了最有效且最具临床转化潜力的药物进行进一步的体外和体内评估，以确定其临床应用潜力。 结果：我们的抗癌药物筛选显示，放线菌素D在所有婴儿ALL细胞系中均表现出显著活性。进一步的体外测试发现，该药物在我们所有婴儿ALL细胞系中的半数抑制浓度（IC50）均处于纳摩尔级别的低值范围。与目前用于治疗婴儿ALL的常规化疗药物联合测试表明，放线菌素D与阿糖胞苷具有相加效应。体内评估确定放线菌素D的最大耐受剂量为36微克/千克，更高剂量治疗会产生不可接受的毒性。在患者来源异种移植模型中，每周一次或两次给予18微克/千克剂量的治疗，虽效果有限但产生了显著的生存获益。 结论：放线菌素D广泛用于儿童实体瘤治疗，在此背景下用于婴儿治疗时具有可接受的安全性。然而，尽管该药物易于转化且体外细胞毒性表现良好，但其体内疗效有限，因此不作为整合入婴儿ALL治疗方案的优先候选药物。
Preclinical Assessment of Dactinomycin inKMT2A-Rearranged Infant Acute Lymphoblastic Leukemia
肿瘤(癌症)患者之家