University of California, San Francisco, San Francisco, CA 94158, USA.
Neuro Oncol. 2012 Mar;14(3):315-25. doi: 10.1093/neuonc/nor209. Epub 2011 Dec 12.
The phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is activated in more than88% of glioblastomas (GBM). New drugs targeting this pathway are currently in clinical trials. However, noninvasive assessment of treatment response remains challenging. By using magnetic resonance spectroscopy (MRS), PI3K/Akt/mTOR pathway inhibition was monitored in 3 GBM cell lines (GS-2, GBM8, and GBM6; each with a distinct pathway activating mutation) through the measurement of 2 mechanistically linked MR biomarkers: phosphocholine (PC) and hyperpolarized lactate.(31)P MRS studies showed that treatment with the PI3K inhibitor LY294002 induced significant decreases in PC to 34 %± 9% of control in GS-2 cells, 48% ± 5% in GBM8, and 45% ± 4% in GBM6. The mTOR inhibitor everolimus also induced a significant decrease in PC to 62% ± 14%, 57% ± 1%, and 58% ± 1% in GS-2, GBM8, and GBM6 cells, respectively. Using hyperpolarized (13)C MRS, we demonstrated that hyperpolarized lactate levels were significantly decreased following PI3K/Akt/mTOR pathway inhibition in all 3 cell lines to 51% ± 10%, 62% ± 3%, and 58% ± 2% of control with LY294002 and 72% ± 3%, 61% ± 2%, and 66% ± 3% of control with everolimus in GS-2, GBM8, and GBM6 cells, respectively. These effects were mediated by decreases in the activity and expression of choline kinase α and lactate dehydrogenase, which respectively control PC and lactate production downstream of HIF-1. Treatment with the DNA damaging agent temozolomide did not have an effect on either biomarker in any cell line. This study highlights the potential of PC and hyperpolarized lactate as noninvasive MR biomarkers of response to targeted inhibitors in GBM.
磷脂酰肌醇-3-激酶/蛋白激酶 B/哺乳动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）信号通路在超过 88%的胶质母细胞瘤（GBM）中被激活。目前，有针对该通路的新药正在临床试验中。然而，治疗反应的无创评估仍然具有挑战性。通过磁共振波谱（MRS），通过测量 2 种具有机制联系的 MR 生物标志物：磷酸胆碱（PC）和极化乳酸，可以监测 3 种 GBM 细胞系（GS-2、GBM8 和 GBM6；每个细胞系都有独特的通路激活突变）中的 PI3K/Akt/mTOR 通路抑制作用。(31)P MRS 研究表明，PI3K 抑制剂 LY294002 治疗可使 GS-2 细胞中的 PC 显著降低至对照的 34%±9%，GBM8 中为 48%±5%，GBM6 中为 45%±4%。mTOR 抑制剂依维莫司也可使 GS-2、GBM8 和 GBM6 细胞中的 PC 分别显著降低至 62%±14%、57%±1%和 58%±1%。使用极化（13)C MRS，我们证明在所有 3 种细胞系中，PI3K/Akt/mTOR 通路抑制后，极化乳酸水平均显著降低，分别为 LY294002 治疗的对照的 51%±10%、62%±3%和 58%±2%，以及依维莫司治疗的对照的 72%±3%、61%±2%和 66%±3%。这些作用是通过降低胆碱激酶 α 和乳酸脱氢酶的活性和表达介导的，它们分别控制 HIF-1 下游的 PC 和乳酸的产生。DNA 损伤剂替莫唑胺治疗对任何细胞系中的任何一种生物标志物均无影响。本研究强调了 PC 和极化乳酸作为胶质母细胞瘤靶向抑制剂治疗反应的无创性 MR 生物标志物的潜力。
