Gurbani Saumya S, Yoon Younghyoun, Weinberg Brent D, Salgado Eric, Press Robert H, Cordova J Scott, Ramesh Karthik K, Liang Zhongxing, Velazquez Vega Jose, Voloschin Alfredo, Olson Jeffrey J, Schreibmann Eduard, Shim Hyunsuk, Shu Hui-Kuo G
Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA.
Tomography. 2019 Mar;5(1):53-60. doi: 10.18383/j.tom.2018.00031.
Histone deacetylases regulate a wide variety of cellular functions and have been implicated in redifferentiation of various tumors. Histone deacetylase inhibitors (HDACi) are potential pharmacologic agents to improve outcomes for patients with gliomas. We assessed the therapeutic efficacy of belinostat (PXD-101), an HDACi with blood-brain barrier permeability. Belinostat was first tested in an orthotopic rat glioma model to assess in vivo tumoricidal effect. Our results showed that belinostat was effective in reducing tumor volume in the orthotopic rat glioma model in a dose-dependent manner. We also tested the antidepression activity of belinostat in 2 animal models of depression and found it to be effective. Furthermore, we confirmed that myo-inositol levels improved by belinostat treatment in vitro. In a human pilot study, it was observed that belinostat in combination with chemoradiation may delay initial recurrence of disease. Excitingly, belinostat significantly improved depressive symptoms in patients with glioblastoma compared with control subjects. Finally, spectroscopic magnetic resonance imaging of 2 patient cases from this pilot study are presented to indicate how spectroscopic magnetic resonance imaging can be used to monitor metabolite response and assess treatment effect on whole brain. This study highlights the potential of belinostat to be a synergistic therapeutic agent in the treatment of gliomas.
组蛋白去乙酰化酶调节多种细胞功能，并与各种肿瘤的再分化有关。组蛋白去乙酰化酶抑制剂（HDACi）是改善胶质瘤患者预后的潜在药物。我们评估了具有血脑屏障通透性的HDACi贝利司他（PXD-101）的治疗效果。贝利司他首先在原位大鼠胶质瘤模型中进行测试，以评估其体内杀瘤效果。我们的结果表明，贝利司他在原位大鼠胶质瘤模型中能以剂量依赖的方式有效减少肿瘤体积。我们还在两种抑郁症动物模型中测试了贝利司他的抗抑郁活性，发现它是有效的。此外，我们证实了贝利司他在体外处理可提高肌醇水平。在一项人体初步研究中，观察到贝利司他联合放化疗可能会延迟疾病的初始复发。令人兴奋的是，与对照组相比，贝利司他显著改善了胶质母细胞瘤患者的抑郁症状。最后，展示了该初步研究中2例患者的磁共振波谱成像，以说明磁共振波谱成像如何用于监测代谢物反应并评估对全脑的治疗效果。这项研究突出了贝利司他作为胶质瘤治疗中协同治疗药物的潜力。
