Persico Pasquale, Lorenzi Elena, Losurdo Agnese, Dipasquale Angelo, Di Muzio Antonio, Navarria Pierina, Pessina Federico, Politi Letterio Salvatore, Lombardi Giuseppe, Santoro Armando, Simonelli Matteo
Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Milan, Italy.
Oncology Department, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy.
Cancers (Basel). 2022 Feb 22;14(5):1125. doi: 10.3390/cancers14051125.
Mutations in isocitrate dehydrogenase ( and its homolog are considered an earliest "driver" genetic event during gliomagenesis, representing now the molecular hallmark of lower-grade gliomas (LGGs). -mutated genes encode for a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG), which accumulates to high concentrations and alters cellular epigenetics and metabolism. Targeting IDH mutations is the first attempt to apply "precision oncology" in LGGs. Two distinct strategies have been proposed so far and are under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the function of mutant IDH enzyme; (ii) exploiting the selective epigenetic and metabolic cellular vulnerabilities as a consequence of 2-HG accumulation. The present review describes the physiopathological mechanisms by which mutations lead to tumorigenesis, discussing their prognostic significance and pivotal role in the gliomas diagnostic classification system. We critically review preclinical evidence and available clinical data of first-generation mutant-selective IDH inhibitors and novel IDH-targeted vaccines. Finally, as an alternative and attractive approach, we present the rationale to take advantage of selective 2-HG related epigenetic and metabolic weaknesses. The results of ongoing clinical trials will help us clarify the complex scenario of IDH-targeted therapeutic approaches in gliomas.
异柠檬酸脱氢酶（及其同源物）的突变被认为是胶质瘤发生过程中最早的“驱动”基因事件，目前代表着低级别胶质瘤（LGG）的分子标志。IDH突变基因编码一种新形态酶，该酶将α-酮戊二酸转化为致癌代谢物D-2-羟基戊二酸（2-HG），其积累至高浓度并改变细胞表观遗传学和代谢。针对IDH突变是在LGG中应用“精准肿瘤学”的首次尝试。目前已提出两种不同策略并正在进行深入临床研究：（i）通过直接阻断突变IDH酶的功能来减少肿瘤内2-HG的量；（ii）利用2-HG积累导致的选择性表观遗传学和代谢细胞易损性。本综述描述了IDH突变导致肿瘤发生的生理病理机制，讨论了它们在胶质瘤诊断分类系统中的预后意义和关键作用。我们批判性地回顾了第一代突变体选择性IDH抑制剂和新型IDH靶向疫苗的临床前证据和现有临床数据。最后，作为一种替代且有吸引力的方法，我们提出利用与2-HG相关的选择性表观遗传学和代谢弱点的基本原理。正在进行的临床试验结果将帮助我们阐明胶质瘤中IDH靶向治疗方法的复杂情况。
