Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA.
Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA.
Tomography. 2023 May 4;9(3):942-954. doi: 10.3390/tomography9030077.
Histone deacetylase inhibitors (HDACis) are drugs that target the epigenetic state of cells by modifying the compaction of chromatin through effects on histone acetylation. Gliomas often harbor a mutation of isocitrate dehydrogenase (IDH) 1 or 2 that leads to changes in their epigenetic state presenting a hypermethylator phenotype. We postulated that glioma cells with IDH mutation, due to the presence of epigenetic changes, will show increased sensitivity to HDACis. This hypothesis was tested by expressing mutant IDH1 with a point alteration-converting arginine 132 to histidine-within glioma cell lines that contain wild-type IDH1. Glioma cells engineered to express mutant IDH1 produced D-2-hydroxyglutarate as expected. When assessed for response to the pan-HDACi drug belinostat, mutant IDH1-expressing glioma cells were subjected to more potent inhibition of growth than the corresponding control cells. Increased sensitivity to belinostat correlated with the increased induction of apoptosis. Finally, a phase I trial assessing the addition of belinostat to standard-of-care therapy for newly diagnosed glioblastoma patients included one patient with a mutant IDH1 tumor. This mutant IDH1 tumor appeared to display greater sensitivity to the addition of belinostat than the other cases with wild-type IDH tumors based on both standard magnetic resonance imaging (MRI) and advanced spectroscopic MRI criteria. These data together suggest that IDH mutation status within gliomas may serve as a biomarker of response to HDACis.
组蛋白去乙酰化酶抑制剂 (HDACi) 是一类通过影响组蛋白乙酰化来改变染色质的紧缩从而靶向细胞表观遗传状态的药物。神经胶质瘤常携带异柠檬酸脱氢酶 (IDH) 1 或 2 的突变，导致其表观遗传状态发生变化，呈现出高度甲基化表型。我们推测由于存在表观遗传变化，具有 IDH 突变的神经胶质瘤细胞对 HDACi 会更敏感。这一假设通过在含有野生型 IDH1 的神经胶质瘤细胞系中表达具有点突变的 IDH1，将精氨酸 132 转化为组氨酸，从而检测到。正如预期的那样，表达突变 IDH1 的神经胶质瘤细胞产生了 D-2-羟基戊二酸。当评估对 pan-HDACi 药物 belinostat 的反应时，与相应的对照细胞相比，表达突变 IDH1 的神经胶质瘤细胞的生长抑制更为强烈。对 belinostat 的敏感性增加与细胞凋亡的诱导增加相关。最后，一项评估 belinostat 联合标准治疗方案用于新诊断的胶质母细胞瘤患者的 I 期试验包括一名携带突变 IDH1 肿瘤的患者。根据标准磁共振成像 (MRI) 和先进的光谱 MRI 标准，与携带野生型 IDH 肿瘤的其他病例相比，该突变 IDH1 肿瘤似乎对 belinostat 的添加表现出更高的敏感性。这些数据共同表明，神经胶质瘤中的 IDH 突变状态可能作为对 HDACi 反应的生物标志物。
