Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate.
Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate.
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DOI：
10.1038/s41467-018-03905-6
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发表时间：
2018-04-16
影响因子：
16.6
通讯作者：
Batchelor TT
中科院分区：
文献类型：
--
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
突变型异柠檬酸脱氢酶1（IDH 1）的抑制剂最近进入神经胶质瘤治疗的临床试验。突变IDH 1产生高水平的2-羟基谷氨酸（2 HG），被认为是通过基因表达的表观遗传修饰启动肿瘤发生。在这项研究中，我们显示了一种新的突变IDH 1抑制剂在胶质瘤患者中的药效学的初步证据，使用非侵入性的3D MR光谱成像的2 HG。我们的1期临床试验结果表明，治疗1周后，2 HG水平迅速下降70%（CI 13%，P = 0.019）。重要的是，突变IDH 1的抑制可能导致肿瘤代谢的重编程，这由谷胱甘肽、谷氨酰胺、谷氨酸和乳酸的同时变化所暗示。代谢变化和扩散MRI之间的负相关性表明对肿瘤细胞密度的影响。我们展示了一种可行的放射性药物动力学方法，以支持针对IDH 1/2突变的合理设计的药物的快速临床转化，用于胶质瘤患者的个性化和精准医学。突变型异柠檬酸脱氢酶1（IDH 1）的抑制剂最近进入了治疗神经胶质瘤的临床试验。在此，作者应用MRS成像方法对8例突变型IDH 1胶质瘤患者进行2 HG检测并评估突变型IDH 1抑制剂（IDH 305）的药效学作用。
Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. Mutant IDH1 produces high levels of 2-hydroxyglurate (2HG), thought to initiate oncogenesis through epigenetic modifications of gene expression. In this study, we show the initial evidence of the pharmacodynamics of a new mutant IDH1 inhibitor in glioma patients, using non-invasive 3D MR spectroscopic imaging of 2HG. Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0.019) after 1 week of treatment. Importantly, inhibition of mutant IDH1 may lead to the reprogramming of tumor metabolism, suggested by simultaneous changes in glutathione, glutamine, glutamate, and lactate. An inverse correlation between metabolic changes and diffusion MRI indicates an effect on the tumor-cell density. We demonstrate a feasible radiopharmacodynamics approach to support the rapid clinical translation of rationally designed drugs targeting IDH1/2 mutations for personalized and precision medicine of glioma patients. Inhibitors of mutant isocitrate dehydrogenase 1 (IDH1) entered recently clinical trials for treatment of gliomas. Here, the authors apply a MRS imaging method for 2HG detection and assessement of the pharmacodynamic effects of the mutant IDH1 inhibitor (IDH305) in 8 mutant IDH1 glioma patients.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Emir UE;Larkin SJ;de Pennington N;Voets N;Plaha P;Stacey R;Al-Qahtani K;Mccullagh J;Schofield CJ;Clare S;Jezzard P;Cadoux-Hudson T;Ansorge O
通讯作者：
Ansorge O
影响因子：
12.7
作者：
Capper, David;Zentgraf, Hanswalter;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
影响因子：
3.9
作者：
Chi, Andrew S.;Batchelor, Tracy T.;Dias-Santagata, Dora;Borger, Darrell;Stiles, Charles D.;Wang, Daphne L.;Curry, William T.;Wen, Patrick Y.;Ligon, Keith L.;Ellisen, Leif;Louis, David N.;Iafrate, A. John
通讯作者：
Iafrate, A. John
影响因子：
17.1
作者：
Andronesi OC;Kim GS;Gerstner E;Batchelor T;Tzika AA;Fantin VR;Vander Heiden MG;Sorensen AG
通讯作者：
Sorensen AG