MR Studies of Glioblastoma Models Treated with Dual PI3K/mTOR Inhibitor and Temozolomide:Metabolic Changes Are Associated with Enhanced Survival.
MR Studies of Glioblastoma Models Treated with Dual PI3K/mTOR Inhibitor and Temozolomide:Metabolic Changes Are Associated with Enhanced Survival.
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DOI：
10.1158/1535-7163.mct-15-0769
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发表时间：
2016-05
影响因子：
5.7
通讯作者：
Ronen SM
中科院分区：
文献类型：
--
作者：
Radoul M;Chaumeil MM;Eriksson P;Wang AS;Phillips JJ;Ronen SM
目前胶质母细胞瘤（GBM）的标准治疗是手术切除、放疗和替莫唑胺（TMZ）治疗。然而，对当前疗法的抗性和复发是常见的。为了提高生存率，靶向磷酸肌醇-3-激酶（PI 3 K）信号通路的药物目前正在临床试验中，该信号通路在约88%的GBM中被激活。这种疗法的挑战是并不总是观察到肿瘤缩小。因此，需要新的成像方法来监测对治疗的反应并预测存活率。本研究的目的是确定超极化13 C磁共振波谱成像（MRSI）和1H磁共振波谱（MRS）是否可用于监测第二代双重PI 3 K/mTOR抑制剂voxtalisib（XL 765，SAR 245409）单独或与TMZ联合治疗的反应。我们研究了小鼠GS-2和U87-MG GBM原位肿瘤，并使用磁共振成像（MRI）、超极化13 C MRSI和1H MRS监测治疗效果。在我们的研究中，1H MRS不能预测肿瘤对治疗的反应。然而，在我们的两种模型中，我们观察到与对照相比，在用voxtalisib、TMZ或联合治疗的动物中超极化乳酸与丙酮酸的比率显著较低。在MRI可检测到肿瘤大小变化之前观察到这种代谢改变，与药物作用一致，并与提高动物存活率相关。我们的研究结果证实了超极化乳酸-丙酮酸比率作为非侵入性评估GBM患者新兴疗法效果的生物标志物的潜在转化价值。
Current standard of care for glioblastoma (GBM) is surgical resection, radiation, and treatment with Temozolomide (TMZ). However, resistance to current therapies and recurrence are common. To improve survival, agents that target the phosphoinositide-3-kinase (PI3K) signaling pathway, which is activated in ∼88% of GBM, are currently in clinical trials. A challenge with such therapies is that tumor shrinkage is not always observed. New imaging methods are therefore needed to monitor response to therapy and predict survival. The goal of this study was to determine whether hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and 1H magnetic resonance spectroscopy (MRS) can be used to monitor response to the second-generation dual PI3K/mTOR inhibitor voxtalisib (XL765, SAR245409), alone or in combination with TMZ. We investigated GS-2 and U87-MG GBM orthotopic tumors in mice, and used magnetic resonance imaging (MRI), hyperpolarized 13C MRSI and 1H MRS to monitor the effects of treatment. In our study, 1H MRS could not predict tumor response to therapy. However, in both our models, we observed a significantly lower hyperpolarized lactate-to-pyruvate ratio in animals treated with voxtalisib, TMZ, or combination therapy, when compared to controls. This metabolic alteration was observed prior to MRI-detectable changes in tumor size, was consistent with drug-action, and was associated with enhanced animal survival. Our findings confirm the potential translational value of the hyperpolarized lactate-to-pyruvate ratio as a biomarker for noninvasively assessing the effects of emerging therapies for patients with GBM.