PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival
PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival
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DOI：
10.1038/s41598-019-47021-x
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发表时间：
2019-07-19
影响因子：
4.6
通讯作者：
Ronen, Sabrina M.
中科院分区：
文献类型：
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作者：
Batsios, Georgios;Viswanath, Pavithra;Ronen, Sabrina M.
70-90%的低级别胶质瘤和继发性胶质母细胞瘤以异柠檬酸脱氢酶1 （IDHmut）突变为特征。IDHmut产生肿瘤代谢物2-羟基戊二酸（2HG），在这些肿瘤中驱动肿瘤发生。磷酸肌醇-3-激酶(PI3K)/雷帕霉素（mTOR）途径的哺乳动物靶点是IDHmut胶质瘤的一个有吸引力的治疗靶点，但缺乏药物靶点调节的非侵入性指标。因此，本研究的目的是鉴定与IDHmut胶质瘤对双PI3K/(mTOR)抑制剂XL765反应相关的磁共振波谱（MRS）可检测的代谢生物标志物。两种表达IDHmut的转基因细胞系的H-1-MRS显示，XL765诱导了包括2HG在内的几种细胞内代谢物的显著降低。重要的是，对原位IDHmut肿瘤模型的检查显示，XL765治疗后动物存活率的提高与体内H-1-MRS检测到的2HG显著降低有关，但与肿瘤生长的显著抑制无关。需要进一步验证，但我们的研究结果表明，2HG可以作为IDHmut胶质瘤对PI3K/mTOR抑制反应的潜在无创磁共振检测代谢生物标志物。
70-90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase 1 (IDHmut). IDHmut produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis in these tumors. The phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway represents an attractive therapeutic target for IDHmut gliomas, but noninvasive indicators of drug target modulation are lacking. The goal of this study was therefore to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers associated with IDHmut glioma response to the dual PI3K/(mTOR) inhibitor XL765. H-1-MRS of two cell lines genetically modified to express IDHmut showed that XL765 induced a significant reduction in several intracellular metabolites including 2HG. Importantly, examination of an orthotopic IDHmut tumor model showed that enhanced animal survival following XL765 treatment was associated with a significant in vivo H-1-MRS detectable reduction in 2HG but not with significant inhibition in tumor growth. Further validation is required, but our results indicate that 2HG could serve as a potential noninvasive MRS-detectable metabolic biomarker of IDHmut glioma response to PI3K/mTOR inhibition.