Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States.
Department of Neurological Surgery, Helen Diller Research Center, 1450 3rd Street, University of California, 94143, San Francisco, CA, United States.
Sci Rep. 2019 Jul 19;9(1):10521. doi: 10.1038/s41598-019-47021-x.
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-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-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.
70-90%的低级别胶质瘤和继发性胶质母细胞瘤的特征是异柠檬酸脱氢酶 1（IDHmut）发生突变。IDHmut 产生致癌代谢物 2-羟戊二酸（2HG），这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）途径的哺乳动物靶蛋白代表了 IDHmut 胶质瘤有吸引力的治疗靶点，但缺乏针对药物靶点调节的非侵入性指标。因此，本研究的目的是确定与 IDHmut Glioma 对双重 PI3K/（mTOR）抑制剂 XL765 反应相关的磁共振波谱（MRS）可检测代谢生物标志物。两种细胞系的 H-MRS 经过基因修饰表达 IDHmut 显示 XL765 诱导几种细胞内代谢物（包括 2HG）的显著减少。重要的是，对 IDHmut 肿瘤模型的检查表明，XL765 治疗后动物存活率的提高与 2HG 的体内 H-MRS 检测到的显著减少相关，而与肿瘤生长的显著抑制无关。需要进一步验证，但我们的结果表明，2HG 可以作为 IDHmut 胶质瘤对 PI3K/mTOR 抑制反应的潜在非侵入性 MRS 可检测代谢生物标志物。
