Di Gialleonardo Valentina, Aldeborgh Hannah N, Miloushev Vesselin, Folkers Kelly M, Granlund Kristin, Tap William D, Lewis Jason S, Weber Wolfgang A, Keshari Kayvan R
Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Medicine Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Res. 2017 Jun 1;77(11):3113-3120. doi: 10.1158/0008-5472.CAN-16-3310. Epub 2017 Apr 6.
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 multimodality approach to evaluate the phenotypic effects and metabolic changes that 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 , followed by cell growth inhibition. , we observed a similar quantitative reduction in lactate production as monitored by hyperpolarized MRI, also followed by tumor size changes. This noninvasive imaging method could distinguish reduced cell proliferation from induction of cell death. Our results illustrate the use of hyperpolarized MRI as a sensitive technique to monitor drug-induced perturbation of the PI3K/mTOR pathway in sarcomas. .
在PI3K和mTOR常过度激活的肉瘤中，预测雷帕霉素类药物反应的生物标志物可以改善将有反应的患者合理纳入临床试验的情况。PI3K/mTOR信号通路激活通过调节癌细胞的无氧糖酵解来驱动能量产生，这提示了一种监测策略的途径。在本研究中，我们采用多模态方法来评估PI3K/mTOR信号通路受抑制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治疗，评估了其在调节人类肉瘤糖酵解中的核心作用。我们观察到乳酸生成总体减少，随后细胞生长受到抑制。同样，通过超极化磁共振成像监测，我们观察到乳酸生成有类似的定量减少，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。我们的结果说明了超极化磁共振成像作为一种敏感技术，可用于监测肉瘤中PI3K/mTOR信号通路的药物诱导扰动。
