Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications
Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications
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DOI：
10.1038/nm1487
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发表时间：
2006-10-01
期刊：
影响因子：
82.9
通讯作者：
Loeffler, Markus
中科院分区：
文献类型：
--
作者：
Roeder, Ingo;Horn, Matthias;Loeffler, Markus
酪氨酸激酶抑制剂伊马替尼治疗慢性髓性白血病（CML）代表了分子靶向癌症治疗的成功应用。快速的血液学和细胞遗传学反应可以诱导大多数人，甚至在晚期疾病。然而，完全根除以表达BCR-ABL1融合蛋白为特征的恶性细胞是罕见的。恶性克隆持续存在的原因目前尚不清楚，这给临床医生和生物学家带来了巨大的挑战。基于定量解释广泛现象的数学建模方法，我们展示了两个独立的数据集，在伊马替尼治疗CML期间临床观察到的BCR-ABL1转录动力学可以一致地通过伊马替尼对增殖性白血病干细胞的选择性功能作用来解释。我们的结果表明，伊马替尼的一般潜力诱导完全消除恶性克隆。此外，我们预测，在某些情况下，伊马替尼的治疗效果可以通过与促增殖治疗策略的结合而加速。
Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitor imatinib represents a successful application of molecularly targeted cancer therapy. A rapid hematologic and cytogenetic response can be induced in the majority of people, even in advanced disease. However, complete eradication of malignant cells, which are characterized by the expression of the BCR-ABL1 fusion protein, is rare. Reasons for the persistence of the malignant clone are currently not known and provide a substantial challenge for clinicians and biologists. Based on a mathematical modeling approach that quantitatively explains a broad range of phenomena, we show for two independent datasets that clinically observed BCR-ABL1 transcript dynamics during imatinib treatment of CML can consistently be explained by a selective functional effect of imatinib on proliferative leukemia stem cells. Our results suggest the general potential of imatinib to induce a complete elimination of the malignant clone. Moreover, we predict that the therapeutic benefit of imatinib can, under certain circumstances, be accelerated by combination with proliferation-stimulating treatment strategies.