Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Curr Cancer Drug Targets. 2020;20(7):490-500. doi: 10.2174/1568009620666200424145622.
The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.
通过 DNA 测序对急性髓系白血病（AML）进行基因组特征分析，揭示了疾病的亚类，这些亚类具有不同的驱动突变，可能对靶向治疗有反应。大约 15-23%的 AML 基因组中存在异柠檬酸脱氢酶（IDH1 或 IDH2）两种同工酶之一的突变。这些酶是细胞基本代谢的组成性介质，但在癌症中，它们的突变形式合成一种异常代谢物 2-羟戊二酸，反过来又作为多种基因调节酶的竞争性抑制剂。因此，白血病 IDH 突变导致基因组结构和基因活性发生变化，最终导致正常髓样分化停滞。这些发现促使开发了一类新的选择性小分子，它们能够抑制突变的 IDH 酶，同时保留正常的细胞代谢。这些药物在动物模型和早期临床试验中显示出有希望的抗白血病活性，目前正在进行 3 期研究。本综述将重点介绍不断增加的评估 IDH 抑制剂治疗 IDH 突变 AML 的临床前和临床数据。这些数据表明，诱导细胞分化是 IDH 抑制剂临床疗效的核心机制，同时也介导了经历 IDH 分化综合征的患者的毒性。正在进行的试验正在研究 IDH 抑制剂与其他 AML 疗法联合应用的疗效，以评估潜在的协同组合，并确定 IDH 抑制剂在现有标准治疗方案中的适当位置。
