A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit.
A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit.
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DOI：
10.1038/s41598-017-14065-w
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发表时间：
2017-10-23
影响因子：
4.6
通讯作者：
Lam MH
中科院分区：
文献类型：
--
作者：
Kopinja J;Sevilla RS;Levitan D;Dai D;Vanko A;Spooner E;Ware C;Forget R;Hu K;Kral A;Spacciapoli P;Kennan R;Jayaraman L;Pucci V;Perera S;Zhang W;Fischer C;Lam MH
IDH1基因突变在人脑胶质瘤中非常普遍。一线治疗是放射治疗，许多患者经常放弃放射治疗以避免与治疗相关的疾病。IDH1突变在脑胶质瘤中的高度流行突出了脑穿透性IDH1突变选择性抑制剂作为替代治疗选择的必要性。在这里，我们探索了这种抑制物在IDH1突变患者衍生模型中的应用，以评估与颅内2-HG抑制相关的潜在治疗益处。对突变的IDH1细胞系模型的处理导致了体内和体外细胞内2-HG水平的下降。有趣的是，抑制2-HG的产生对IDH1突变型胶质瘤细胞的体外增殖没有影响。相比之下，IDH1突变选择性抑制剂在体内提供了相当大的存活益处。然而，即使肿瘤内2-HG的产生几乎完全被抑制，并不是所有的突变型胶质瘤模型对治疗都有反应。结果表明，在IDH1突变的胶质瘤中，用脑穿透抑制剂干扰2-HG的产生可能会对患者产生实质性的好处。
Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition. Treatment of mutant IDH1 cell line models led to a decrease in intracellular 2-HG levels both in vitro and in vivo. Interestingly, inhibition of 2-HG production had no effect on in vitro IDH1 mutant glioma cell proliferation. In contrast, IDH1 mutant-selective inhibitors provided considerable survival benefit in vivo. However, even with near complete inhibition of intratumoral 2-HG production, not all mutant glioma models responded to treatment. The results suggest that disruption of 2-HG production with brain-penetrant inhibitors in IDH1 mutant gliomas may have substantial patient benefit.
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影响因子：
16.6
作者：
Guilhamon P;Eskandarpour M;Halai D;Wilson GA;Feber A;Teschendorff AE;Gomez V;Hergovich A;Tirabosco R;Fernanda Amary M;Baumhoer D;Jundt G;Ross MT;Flanagan AM;Beck S
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Beck S
影响因子：
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影响因子：
50.3
作者：
Xu W;Yang H;Liu Y;Yang Y;Wang P;Kim SH;Ito S;Yang C;Wang P;Xiao MT;Liu LX;Jiang WQ;Liu J;Zhang JY;Wang B;Frye S;Zhang Y;Xu YH;Lei QY;Guan KL;Zhao SM;Xiong Y
通讯作者：
Xiong Y
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
12.7
作者：
Capper, David;Zentgraf, Hanswalter;von Deimling, Andreas
通讯作者：
von Deimling, Andreas