Targeted Differentiation Therapy with Mutant IDH Inhibitors: Early Experiences and Parallels with Other Differentiation Agents
Targeted Differentiation Therapy with Mutant IDH Inhibitors: Early Experiences and Parallels with Other Differentiation Agents
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DOI：
10.1146/annurev-cancerbio-050216-122051
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Yen, Katharine
中科院分区：
文献类型：
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作者：
Stein, Eytan;Yen, Katharine
异柠檬酸脱氢酶（IDH）1和2基因的体细胞突变已在多种血液肿瘤和实体瘤中描述，并赋予功能获得，允许产生癌代谢产物（R）2-羟基戊二酸（2-HG）。2-HG积累诱导DNA和组蛋白高甲基化和改变基因表达，最终导致细胞分化阻滞。概念验证的临床前工作表明，突变IDH（mIDH）酶的靶向抑制是一种可行的治疗策略，基于抑制mIDH酶阻断2-HG产生的假设，导致适当的甲基化状态和细胞分化的开始。靶向抑制剂的临床开发项目正在进行中，mIDH急性髓细胞白血病患者的初步数据表明，这些抑制剂可作为分化剂。在这里，我们审查了使用分化剂治疗血液和实体瘤，并讨论了临床前和早期临床证据表明，mIDH抑制剂介导的抗肿瘤作用，通过诱导分化。
Somatic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes have been described in multiple hematologic and solid tumors, and confer a gain of function, permitting the production of the oncometabolite (R)2-hydroxyglutarate (2-HG). 2-HG accumulation induces DNA and histone hypermethylation and altered gene expression, ultimately resulting in a block in cellular differentiation. Proof-of-concept preclinical work demonstrated that targeted inhibition of the mutant IDH (mIDH) enzyme is a feasible therapeutic strategy, based on the hypothesis that inhibition of the mIDH enzyme blocks 2-HG production, resulting in an appropriate methylation state and the onset of cellular differentiation. Clinical development programs for targeted inhibitors are underway, and preliminary data in patients with mIDH acute myeloid leukemia suggest that these inhibitors act as differentiation agents. Here we review the use of differentiation agents for the treatment of hematologic and solid tumors and discuss the preclinical and early clinical evidence that mIDH inhibitors mediate antitumor effects through the induction of differentiation.