Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG-Expressing Glioblastoma Patients.
Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG-Expressing Glioblastoma Patients.
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DOI：
10.1158/1078-0432.ccr-15-3169
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Kuo JS
中科院分区：
文献类型：
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作者：
Pointer KB;Clark PA;Eliceiri KW;Salamat MS;Robertson GA;Kuo JS
胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤，中位生存期不到两年。需要更有效的治疗方法来改善临床结果。从患者GBM中分离胶质母细胞瘤患者来源的细胞（GPDC）并植入小鼠中以形成异种移植物。免疫组化检测hERG表达和肿瘤增殖。用hERG阻断剂E-4031对hERG高表达和低表达细胞系进行成球试验。使用GBM TMA（115例患者）将hERG表达与患者生存率相关联。分析临床数据，以确定患者生存期是否受到hERG抑制药物偶然给药的影响，以及患者GBM hERG表达水平的相关影响。在具有较高增殖指数的GBM异种移植物中hERG表达上调。与低hERG表达的GPDC相比，当用hERG抑制剂处理时，高hERG表达的GPDC显示球体形成减少。GBM TMA分析显示，hERG高表达与低表达的GBM患者的生存期更差，分别为43.5周与60.9周（p= 0.022）。此外，接受至少一种hERG阻滞剂的患者的生存率高于未接受的患者（p=0.0015）。亚组分析显示，接受hERG阻滞剂治疗的hERG高表达GBM患者的生存率提高（p=0.0458）。接受hERG阻滞剂治疗的低hERG表达GBM患者的生存率无差异（p=0.4136）。我们的研究结果表明，hERG是一种潜在的GBM生存标志物，并且已经批准的具有非致室性心动过速hERG抑制活性的药物可能被重新用作高hERG表达GBM患者的辅助GBM治疗。
Glioblastoma (GBM) is the most malignant primary brain tumor, with a median survival of less than two years. More effective therapeutic approaches are needed to improve clinical outcomes. Glioblastoma patient-derived cells (GPDCs) were isolated from patient GBMs and implanted in mice to form xenografts. Immunohistochemistry was performed for hERG expression and tumor proliferation. Sphere-forming assays with hERG blocker E-4031 were performed on a highand low hERG expressing lines. A GBM TMA (115 patients) was used to correlate hERG expression with patient survival. Clinical data was analyzed to determine if patient survival was affected by incidental administration of hERG inhibitory drugs, and the correlative effect of patient GBM hERG expression levels. hERG expression was upregulated in GBM xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared to low hERG-expressing GPDCs. GBM TMA analysis showed worse survival for GBM patients with high hERG expression versus low expression, 43.5 vs. 60.9 weeks respectively (p= 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared to patients who did not (p=0.0015). Subgroup analysis showed that GBM patients with high hERG expression who received hERG blockers had improved survival (p=0.0458). There was no difference in survival for low hERG-expressing GBM patients who received hERG blockers (p=0.4136). Our findings suggest that hERG is a potential GBM survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be re-purposed as adjuvant GBM therapy in high hERG-expressing GBM patients.