Background:Despite the emergence of new treatment modalities, including targeted therapies that are of benefit to patients whose tumours carry specific mutations, the prognosis for most patients with cholangiocarcinoma remains poor. Novel therapeutic approaches that can benefit the majority of patients whose tumour cells do not carry targetable mutations are urgently needed.Results:To identify mutation-agnostic treatment approaches, we screened a library of well-tolerated off-patent drugs against cholangiocarcinoma cells and normal biliary epithelial cells. The screen identified Niclosamide as a drug that reduces the viability of multiple cholangiocarcinoma cell lines but has a lesser effect on normal primary biliary epithelial cells. Moreover, Niclosamide treatment reduces the growth of cholangiocarcinoma tumour cells as tumour spheroids in vitro and reduces the growth of cholangiocarcinoma cells as tumours in a xenograft mouse model of this disease. Through a proteasome-dependent mechanism, Niclosamide treatment reduces the expression of the Proline-Rich Homeodomain (PRH) protein, a transcription factor which acts as an oncoprotein in cholangiocarcinoma cells. However, PRH knockout does not alter the sensitivity of cholangiocarcinoma cells to Niclosamide, indicating that this drug is not dependent on PRH to reduce cell viability. Interestingly, the CDK4/6 kinase inhibitor Palbociclib selectively reduces the viability of cholangiocarcinoma cell lines compared to normal biliary epithelial cells and, importantly, Palbociclib synergises with Niclosamide to reduce cholangiocarcinoma cell viability in vitro as well as to reduce tumour growth in a mouse xenograft model.Conclusion:These preclinical results suggest that the combination of Niclosamide and an inhibitor of CDK4/6 is worthy of clinical evaluation as a potential treatment for this disease.
背景：尽管出现了包括靶向治疗在内的新型治疗方式，这些治疗对携带特定突变的肿瘤患者有益，但大多数胆管癌患者的预后仍然较差。迫切需要能够使肿瘤细胞不携带可靶向突变的大多数患者受益的新型治疗方法。 结果：为确定不依赖突变的治疗方法，我们筛选了一个耐受性良好且已过专利期的药物库，针对胆管癌细胞和正常胆道上皮细胞进行测试。筛选发现氯硝柳胺是一种能够降低多种胆管癌细胞系活力但对正常原代胆道上皮细胞影响较小的药物。此外，氯硝柳胺处理可在体外减少胆管癌肿瘤细胞作为肿瘤球体的生长，并在该疾病的异种移植小鼠模型中减少胆管癌细胞作为肿瘤的生长。通过蛋白酶体依赖机制，氯硝柳胺处理降低了富含脯氨酸同源结构域（PRH）蛋白的表达，该转录因子在胆管癌细胞中充当癌蛋白。然而，PRH敲除并未改变胆管癌细胞对氯硝柳胺的敏感性，表明该药物不依赖PRH来降低细胞活力。有趣的是，CDK4/6激酶抑制剂帕博西尼与正常胆道上皮细胞相比，选择性地降低了胆管癌细胞系的活力，重要的是，帕博西尼与氯硝柳胺在体外协同作用降低胆管癌细胞活力，并在小鼠异种移植模型中减少肿瘤生长。 结论：这些临床前结果表明，氯硝柳胺与CDK4/6抑制剂的联合使用值得作为该疾病的潜在治疗方法进行临床评估。
肿瘤(癌症)患者之家