Mignion Lionel, Danhier Pierre, Magat Julie, Porporato Paolo E, Masquelier Julien, Gregoire Vincent, Muccioli Giulio G, Sonveaux Pierre, Gallez Bernard, Jordan Bénédicte F
Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique De Louvain (UCL), Avenue Mounier, 73 Box B1.73.08, Brussels, Belgium.
Pole of Pharmacology, Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain (UCL), Avenue Mounier, 52 Box B1.53.09, Brussels, Belgium.
Int J Cancer. 2016 Apr 15;138(8):2043-9. doi: 10.1002/ijc.29932. Epub 2015 Dec 9.
The cholinic phenotype, characterized by elevated phosphocholine and a high production of total-choline (tCho)-containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non-invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate (1)H-MRS and diffusion-weighted MRI (DW-MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H-89, indirect inhibitor sorafenib and down-regulation of choline-kinase α (ChKA) expression using specific short-hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti-ChKA shRNA significantly repressed tumor growth. The increase of apparent-diffusion-coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, (1)H-choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW-MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW-MRI combined to choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling.
胆碱表型以磷酸胆碱升高和含总胆碱（tCho）代谢物的高产量为特征，是癌症的一种代谢标志。它可用于靶向治疗。需要非侵入性成像生物标志物来评估个体对通常不会迅速导致肿瘤缩小的靶向抗癌药物的反应。由于代谢变化可能比肿瘤大小变化在治疗的更早阶段出现，因此本研究的目的是评估氢质子磁共振波谱（1H-MRS）和扩散加权磁共振成像（DW-MRI）作为乳腺肿瘤异种移植中胆碱途径调节后肿瘤反应的标志物。使用直接药理抑制剂H-89、间接抑制剂索拉非尼以及通过特异性短发夹RNA（shRNA）下调胆碱激酶α（ChKA）的表达来实现胆碱激酶活性的抑制。虽然这三种策略在体内均显著降低了肿瘤中的tCho含量，但只有索拉非尼和抗ChKA shRNA显著抑制了肿瘤生长。DW-MRI测量的水的表观扩散系数（ADCw）增加可预测索拉非尼治疗小鼠中诱导的坏死和肿瘤生长的抑制，而H89治疗小鼠中ADC值无变化则预示在肿瘤坏死和肿瘤生长方面无效果。总之，氢质子胆碱波谱可作为胆碱靶向药物的药效学生物标志物，而DW-MRI可作为胆碱靶向治疗有效肿瘤反应的早期标志物。DW-MRI与胆碱波谱相结合可为肿瘤对胆碱信号靶向治疗反应的早期临床评估提供有用的非侵入性标志物。
