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. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. NA.

中文翻译：

---

在胃食管癌患者的临床前和临床环境中使用泛 BCL-2 抑制剂靶向癌症干细胞

目的胃食管癌 (GEC) 对治疗有抵抗力并导致预后不良。癌症干细胞 (CSC) 和抗细胞凋亡途径通常会产生治疗抗性。我们试图在体外、体内和临床试验中阐明 BCL-2 抑制剂 AT101 在 GEC 中的抗肿瘤作用。方法 进行广泛的体外和体内临床前研究，以确定 AT101 靶向 CSCs 和抗凋亡蛋白的作用机制。在标准放化疗中加入 AT-101 完成了 GEC 患者的临床试验试验。结果 在胃癌组织 (GC) 中观察到 BCL-2 和 MCL-1 的过度表达。AT-101 在 MCL-1/BCL-2 高 GC 细胞中诱导细胞凋亡、增殖减少和肿瘤球形成。有趣的是，无论 BCL-2/MCL-1 表达如何，AT101 都会显着下调控制 GEC 细胞系中 CSC 的基因 (YAP-1/Sox9)。向 AT-101 添加多西紫杉醇可增强其抗增殖作用并诱导细胞凋亡作用。体内研究证实，AT101 和多西他赛的组合表现出更强的抗肿瘤活性，同时 CSC 生物标志物 (YAP1/SOX9) 显着减少。在一项试验性临床试验中，13 名食管癌 (EC) 患者在化放疗的同时口服了 AT101。我们在这些患者中观察到显着的临床完全反应和令人鼓舞的总生存期。临床标本分析显示，AT-101 显着降低了经处理的 EC 标本中 CSCs 基因的表达，表明 AT101 的抗肿瘤活性更多地依赖于其抗 CSCs 活性。结论 我们的临床前和临床数据表明，AT-101 通过靶向 CSCs 通路克服了耐药性，这表明 AT101 在 GEC 患者中具有一种新的作用机制。可根据合理要求提供数据。所有与研究相关的数据都包含在文章中或作为补充信息上传。不适用。