IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?
IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?
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DOI：
10.3390/biomedicines9070799
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发表时间：
2021-07-10
期刊：
影响因子：
4.7
通讯作者：
Bagci-Onder T
中科院分区：
文献类型：
--
作者：
Kayabolen A;Yilmaz E;Bagci-Onder T
大约十年前在胶质瘤中发现编码异柠檬酸脱氢酶（IDH）的基因中的点突变，挑战了我们对代谢在肿瘤进展中的作用的观点，并为恶性胶质瘤提供了一种新的分层策略。IDH酶催化异柠檬酸转化为α-酮戊二酸（α-KG），这是柠檬酸循环中的中间体。编码IDH的基因中的特定突变引起产生D-2-羟基戊二酸（2-HG）的新形态酶活性，并导致α-KG依赖性酶（如组蛋白和DNA脱甲基酶）的抑制。因此，染色质结构和基因表达谱在IDH突变型胶质瘤似乎是不同的IDH野生型胶质瘤。IDH突变在低级别胶质瘤（LGG）和继发性胶质母细胞瘤中非常常见，并且它们是驱动肿瘤发生的最早遗传事件之一。因此，抑制LGG中的突变IDH酶被广泛接受为有吸引力的治疗策略。另一方面，IDH突变导致的代谢后果导致肿瘤细胞内的选择性脆弱性，使它们对几种治疗干预更敏感。因此，利用突变IDH酶引起的选择性弱点而不是关闭突变IDH酶可能是另一种有吸引力和有前途的策略。在这里，我们回顾治疗方案，并总结目前的IDH突变型胶质瘤的临床前和临床研究。
Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), an intermediate in the citric acid cycle. Specific mutations in the genes encoding IDHs cause neomorphic enzymatic activity that produces D-2-hydroxyglutarate (2-HG) and result in the inhibition of α-KG-dependent enzymes such as histone and DNA demethylases. Thus, chromatin structure and gene expression profiles in IDH-mutant gliomas appear to be different from those in IDH-wildtype gliomas. IDH mutations are highly common in lower grade gliomas (LGG) and secondary glioblastomas, and they are among the earliest genetic events driving tumorigenesis. Therefore, inhibition of mutant IDH enzymes in LGGs is widely accepted as an attractive therapeutic strategy. On the other hand, the metabolic consequences derived from IDH mutations lead to selective vulnerabilities within tumor cells, making them more sensitive to several therapeutic interventions. Therefore, instead of shutting down mutant IDH enzymes, exploiting the selective vulnerabilities caused by them might be another attractive and promising strategy. Here, we review therapeutic options and summarize current preclinical and clinical studies on IDH-mutant gliomas.
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影响因子：
11.1
作者：
Fack F;Tardito S;Hochart G;Oudin A;Zheng L;Fritah S;Golebiewska A;Nazarov PV;Bernard A;Hau AC;Keunen O;Leenders W;Lund-Johansen M;Stauber J;Gottlieb E;Bjerkvig R;Niclou SP
通讯作者：
Niclou SP
影响因子：
10.5
作者：
Amankulor NM;Kim Y;Arora S;Kargl J;Szulzewsky F;Hanke M;Margineantu DH;Rao A;Bolouri H;Delrow J;Hockenbery D;Houghton AM;Holland EC
通讯作者：
Holland EC
影响因子：
16.6
作者：
Carbonneau, Melissa;Gagne, Laurence M.;Lalonde, Marie-Eve;Germain, Marie-Anne;Motorina, Alena;Guiot, Marie-Christine;Secco, Blandine;Vincent, Emma E.;Tumber, Anthony;Hulea, Laura;Bergeman, Jonathan;Oppermann, Udo;Jones, Russell G.;Laplante, Mathieu;Topisirovic, Ivan;Petrecca, Kevin;Huot, Marc-Etienne;Mallette, Frederick A.
通讯作者：
Mallette, Frederick A.
影响因子：
16.6
作者：
Andronesi OC;Arrillaga-Romany IC;Ly KI;Bogner W;Ratai EM;Reitz K;Iafrate AJ;Dietrich J;Gerstner ER;Chi AS;Rosen BR;Wen PY;Cahill DP;Batchelor TT
通讯作者：
Batchelor TT
影响因子：
4.6
作者：
Batsios, Georgios;Viswanath, Pavithra;Ronen, Sabrina M.
通讯作者：
Ronen, Sabrina M.