急性髓性白血病克隆减少治疗策略的数学建模

IF 2.1 4区 医学 Q3 HEMATOLOGY Leukemia research Pub Date : 2024-03-16 DOI:10.1016/j.leukres.2024.107485
Mia Brunetti , Isabella A. Iasenza , Adrianne L. Jenner , Noël J.-M. Raynal , Kolja Eppert , Morgan Craig
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引用次数: 0

摘要

多年来,确诊为急性髓性白血病(AML)的老年患者的总生存率一直没有明显提高。虽然标准的细胞毒疗法能迅速消灭分裂的髓母细胞,从而诱导病情缓解,但由于存活的白血病干细胞(LSCs)对治疗具有抗药性,可能导致病情复发。因此,抗白血病干细胞策略已成为治疗急性髓细胞白血病的关键目标。我们最近发现,在原发性人类急性髓细胞性白血病8227模型中,以前批准的强心苷和糖皮质激素可靶向富含LSC的CD34细胞,其疗效优于正常造血干细胞(HSCs)。为了将这些发现应用于人类,我们建立了一个干细胞动态数学模型,描述了急性髓细胞性白血病标准治疗后造血干细胞的随机演变。为此,我们整合了群体药代动力学-药效学(PKPD)模型,与常用于AML患者高剂量巩固治疗的阿糖胞苷相比,研究了几种有希望的候选药物的克隆减少潜力。我们的研究结果表明,强心甙类(丙种球蛋白 A、地高辛和乌苯那敏)和糖皮质激素(布地奈德和莫美他松)可通过降低 LSCs 的活力来减少其扩增。虽然我们的模型预测有效剂量的强心苷可能毒性过大,不能用于患者,但模拟结果显示,莫米松可以通过糖皮质激素大幅减少造血干细胞的数量来防止复发。因此,这项研究强调了这些治疗方法在抗LSC策略中的前景,并强调了在急性髓细胞性白血病临床前药物转化中使用定量方法的重要性。
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Mathematical modelling of clonal reduction therapeutic strategies in acute myeloid leukemia

Over the years, the overall survival of older patients diagnosed with acute myeloid leukemia (AML) has not significantly increased. Although standard cytotoxic therapies that rapidly eliminate dividing myeloblasts are used to induce remission, relapse can occur due to surviving therapy-resistant leukemic stem cells (LSCs). Hence, anti-LSC strategies have become a key target to cure AML. We have recently shown that previously approved cardiac glycosides and glucocorticoids target LSC-enriched CD34+ cells in the primary human AML 8227 model with more efficacy than normal hematopoietic stem cells (HSCs). To translate these in vitro findings into humans, we developed a mathematical model of stem cell dynamics that describes the stochastic evolution of LSCs in AML post-standard-of-care. To this, we integrated population pharmacokinetic-pharmacodynamic (PKPD) models to investigate the clonal reduction potential of several promising candidate drugs in comparison to cytarabine, which is commonly used in high doses for consolidation therapy in AML patients. Our results suggest that cardiac glycosides (proscillaridin A, digoxin and ouabain) and glucocorticoids (budesonide and mometasone) reduce the expansion of LSCs through a decrease in their viability. While our model predicts that effective doses of cardiac glycosides are potentially too toxic to use in patients, simulations show the possibility of mometasone to prevent relapse through the glucocorticoid’s ability to drastically reduce LSC population size. This work therefore highlights the prospect of these treatments for anti-LSC strategies and underlines the use of quantitative approaches to preclinical drug translation in AML.

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来源期刊
Leukemia research
Leukemia research 医学-血液学
CiteScore
4.00
自引率
3.70%
发文量
259
审稿时长
1 months
期刊介绍: Leukemia Research an international journal which brings comprehensive and current information to all health care professionals involved in basic and applied clinical research in hematological malignancies. The editors encourage the submission of articles relevant to hematological malignancies. The Journal scope includes reporting studies of cellular and molecular biology, genetics, immunology, epidemiology, clinical evaluation, and therapy of these diseases.
期刊最新文献
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