Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma
Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma
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DOI：
10.1136/gutjnl-2020-321175
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发表时间：
2021-12-01
期刊：
影响因子：
24.5
通讯作者：
Ajani, Jaffer A.
中科院分区：
文献类型：
--
作者：
Song, Shumei;Chen, Qiongrong;Ajani, Jaffer A.
目的胃食管癌（GEC）治疗效果差，预后差。癌症干细胞（CSC）和抗凋亡途径通常赋予治疗抗性。我们试图阐明的BCL-2抑制剂，AT 101在GECin体外，在体内和在一个clinical trials.Methods的抗肿瘤作用进行了广泛的临床前研究，在体外和体内，以建立机制作用AT 101对靶向CSC和抗凋亡蛋白。结果在胃癌组织（GC）中观察到BCL-2和MCL-1的过表达。AT-101诱导MCL-1/BCL-2高GC细胞凋亡，减少增殖和肿瘤球形成。有趣的是，无论BCL-2/MCL-1表达如何，AT 101都显著下调GEC细胞系中控制CSC的基因（雅普-1/Sox 9）。在AT-101中加入多西他赛可增强其抗增殖和诱导凋亡作用。体内研究证实，AT 101和多西他赛联合治疗显示出更强的抗肿瘤活性，同时CSC生物标志物（YAP 1/SOX 9）显著降低。在一项初步临床试验中，13名食管癌（EC）患者接受了口服AT 101同时放化疗。我们在这些患者中观察到显著的临床完全反应和令人鼓舞的总生存率。临床标本分析表明，AT-101显着降低CSCs基因的表达在治疗EC标本表明AT 101的抗肿瘤活性依赖于其anti-CSCs activity.Conclusions我们的临床前和临床数据表明，AT-101克服耐药，通过靶向CSCs通路，提示一种新的机制AT 101在GEC患者的作用。
Objective Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.Methods Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.Results Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.Conclusions Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.