Novel targeted drug therapies for the treatment of childhood acute leukemia.
Novel targeted drug therapies for the treatment of childhood acute leukemia.
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DOI：
10.1586/ehm.09.1
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发表时间：
2009-04-01
影响因子：
2.8
通讯作者：
Reaman GH
中科院分区：
文献类型：
--
作者：
Brown P;Hunger SP;Smith FO;Carroll WL;Reaman GH
儿童急性白血病的治愈率已显著提高到约70%，治疗包括强化细胞毒性化疗，在某些情况下，还包括造血干细胞移植。然而，仍有许多儿童死于疾病或与治疗有关的毒性。即使在治愈的患者中，也可能出现严重的急性和晚期治疗并发症，这种情况并不罕见，而且会使人虚弱。对白血病分子和细胞生物学的进一步了解，以及高通量基因组技术的日益普及，促进了分子靶向治疗的发展，这些治疗可能比标准方法更有效，毒性更小。在这篇文章中，我们回顾了迄今为止在治疗儿童急性白血病方面有前景的药物的进展，包括单克隆抗体、激酶和其他信号分子抑制剂（如BCR-ABL、FLT3、法尼基转移酶、mTOR和γ-分泌酶）、靶向基因表达表观遗传调控的药物（DNA甲基转移酶抑制剂和组蛋白去乙酰化酶抑制剂）和蛋白酶体抑制剂。对于这些类别中的特定药物，我们总结了已发表的临床前数据和已经完成、正在进行或正在计划用于急性白血病儿童的临床试验。最后，我们讨论了分子靶向治疗成功的潜在挑战，包括适当的靶点识别、白血病干细胞的充分靶向、开发协同和耐受的药物组合，以及设计足够有力的临床试验来测试分子定义的患者亚群的疗效。
The cure rates for childhood acute leukemia have dramatically improved to approximately 70% overal, with treatments that include intensive cytotoxic chemotherapy and, in some cases, hematopoietic stem cell transplantation. However, many children still die of their disease or of treatment-related toxicities. Even in patients that are cured, there can be significant and, not uncommonly debilitating, acute and late complications of treatment. Improved understanding of the molecular and cellular biology of leukemia and the increasing availability of high-throughput genomic techniques have facilitated the development of molecularly targeted therapies that have the potential to be more effective and less toxic than the standard approaches. In this article, we review the progress to date with agents that are showing promise in the treatment of childhood acute leukemia, including monoclonal antibodies, inhibitors of kinases and other signaling molecules (e.g., BCR–ABL, FLT3, farnesyltransferase, mTOR and γ-secretase), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors) and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress or are being planned for children with acute leukemia. Finally, we discuss potential challenges to the success of molecularly targeted therapy, including proper target identification, adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.
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影响因子：
30.8
作者：
Armstrong, SA;Staunton, JE;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
51.1
作者：
Den Boer, Monique L.;van Slegtenhorst, Marjon;De Menezes, Renee X.;Cheok, Meyling H.;Buijs-Gladdines, Jessica G. C. A. M.;Peters, Susan T. C. J. M.;Van Zutven, Laura C. M.;Beverloo, H. Berna;Van der Spek, Peter J.;Escherich, Gaby;Horstmann, Martin A.;Janka-Schoub, Gritta E.;Kamps, Willem A.;Evans, William E.;Pieters, Rob
通讯作者：
Pieters, Rob
影响因子：
82.9
作者：
Castor, A;Nilsson, L;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
50.3
作者：
Armstrong, SA;Kung, AL;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
20.3
作者：
Cox, CV;Evely, RS;Blair, A
通讯作者：
Blair, A