Brown Patrick, Hunger Stephen P, Smith Franklin O, Carroll William L, Reaman Gregory H
Departments of Oncology and Pediatrics, Sidney Kimmel Comprehensive Cancer, Center and Johns Hopkins University, School of Medicine, 1650 Orleans Street, CRB1 Room 2M49, Baltimore, MD 21231, USA, Tel.: +1 410 955 8817, ,
Expert Rev Hematol. 2009 Apr 1;2(9):145. doi: 10.1586/ehm.09.1.
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.
儿童急性白血病的治愈率已显著提高，总体治愈率约为70%，治疗方法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，许多儿童仍死于疾病或与治疗相关的毒性反应。即使是治愈的患者，治疗也可能出现严重且常见的、使人衰弱的急慢性并发症。对白血病分子和细胞生物学的深入了解以及高通量基因组技术的日益普及，推动了分子靶向治疗的发展，这种治疗方法可能比标准方法更有效且毒性更小。在本文中，我们回顾了目前在儿童急性白血病治疗中显示出前景的药物的进展，包括单克隆抗体、激酶和其他信号分子（如BCR-ABL、FLT3、法尼基转移酶、mTOR和γ-分泌酶）的抑制剂、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脱乙酰酶抑制剂）以及蛋白酶体抑制剂。对于这些类别中的每种特定药物，我们总结了已发表的临床前数据以及针对急性白血病儿童已完成、正在进行或正在计划的临床试验。最后，我们讨论了分子靶向治疗成功面临的潜在挑战，包括正确的靶点识别、对白血病干细胞的充分靶向、开发协同且可耐受的药物组合以及设计有足够效力的临床试验以测试在分子定义的患者亚组中的疗效。
