Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma.
Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma.
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DOI：
10.1158/0008-5472.can-16-3310
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Keshari KR
中科院分区：
文献类型：
--
作者：
Di Gialleonardo V;Aldeborgh HN;Miloushev V;Folkers KM;Granlund K;Tap WD;Lewis JS;Weber WA;Keshari KR
预测 PI3K 和 mTOR 经常过度激活的肉瘤中 rapalog 反应的生物标志物可以改善临床试验中反应性患者的适当招募。 PI3K/mTOR 通路激活通过调节癌细胞中的无氧糖酵解来驱动能量产生，这表明了一种监测策略的途径。在本研究中，我们采用多模式方法来评估抑制 PI3K/mTOR 通路时发生的表型效应和代谢变化。通过对肉瘤细胞系进行短期和长期雷帕霉素处理来评估其在调节人类肉瘤糖酵解中的核心作用。我们观察到体外乳酸产量总体下降，随后细胞生长受到抑制。在体内，通过超极化 MRI 监测，我们观察到乳酸产生量类似的减少，随后肿瘤大小也发生变化。这种非侵入性成像方法可以区分细胞增殖减少和细胞死亡诱导。我们的结果说明使用超极化 MRI 作为一种敏感技术来监测肉瘤中药物引起的 PI3K/mTOR 通路的扰动。
Biomarkers predicting rapalog responses in sarcomas where PI3K and mTOR are often hyperactivated could improve the suitable recruitment of responsive patients to clinical trials. PI3K/mTOR pathway activation drives energy production by regulating anaerobic glycolysis in cancer cells, suggesting a route toward a monitoring strategy. In this study, we took a multi-modality approach to evaluate the phenotypic effects and metabolic changes which occur with inhibition of the PI3K/mTOR pathway. Its central role in regulating glycolysis in human sarcomas was evaluated by short- and long-term rapamycin treatment in sarcoma cell lines. We observed an overall decrease in lactate production in vitro followed by cell growth inhibition. In vivo we observed a similar quantitative reduction in lactate production as monitored by hyperpolarized MRI, also followed by tumor size changes. This non-invasive imaging method could distinguish reduced cell proliferation from induction of cell death. Our resuits illustrate the use of hyperpolarized MRI as a sensitive technique to monitor drug-induced perturbation of the PI3K/mTOR pathway in sarcomas.