PDF(Pubmed)
Abstract：
In humans, inhibition of Notch oncogenic signaling leads to tumor regression. Preclinical studies indicate that Notch signaling contributes to the maintenance of intestinal homeostasis. Here, we sought to describe the intestinal effects of a first-in-human Notch inhibitor in an indication of refractory cancer. Between 2014 and 2017, adult patients treated for refractory cancer with the novel Notch inhibitor LY3039478 and who had grade ≥ 2 diarrhea were referred to the gastroenterology department of a tertiary hospital in the Paris region of France. Eleven patients (median (range) age: 72 (29-83)) were included in the study. All patients had advanced cancer: adenoid cystic carcinoma (n=3, 27 %), sarcoma (n=3, 27 %), and other types (n=5, 46 %). In all cases, digestive tract endoscopy revealed abundant mucus in the intestinal lumen, and digestive tract biopsies showed an abnormally low proportion of enterocytes and marked elevation of the proportion of pseudostratified goblet cells. Microscopic inflammation was seen in colon biopsies from 2 of the 11 patients (18 %). The clinical, endoscopic and histological abnormalities were dependent on the dose of Notch inhibitor. All patients resolved their digestive signs or symptoms after discontinuing the dose and the median (range) time interval between discontinuation of the Notch inhibitor and resolution of all the gastrointestinal signs and symptoms was 7 days (4-24). Likewise, the median time interval between discontinuation and resolution of the histological abnormalities was 7 days (1-10). Blocking Notch signaling induces secretory cell metaplasia of the intestinal epithelium, which in turn leads to transient diarrhea. Our results confirm the role of Notch signaling in intestinal homeostasis in humans.
摘要：
在人类中,抑制Notch致癌信号导致肿瘤消退。临床前研究表明，Notch信号有助于维持肠道稳态。这里,我们试图描述人类首次使用Notch抑制剂对难治性癌症的肠道作用。在2014年至2017年之间，使用新型Notch抑制剂LY3039478治疗难治性癌症且腹泻≥2级的成年患者被转诊至法国巴黎地区一家三级医院的胃肠病科。研究包括11名患者（中位（范围）年龄：72（29-83））。所有患者均患有晚期癌症：腺样囊性癌（n=3，27％），肉瘤（n=3，27%），和其他类型(n=5，46%)。在所有情况下,消化道内窥镜检查显示肠腔内有丰富的粘液，消化道活检显示肠上皮细胞比例异常低，假分层杯状细胞比例明显升高。在11例患者中的2例（18％）的结肠活检中发现了显微镜下的炎症。临床，内镜和组织学异常取决于Notch抑制剂的剂量.所有患者在停止剂量后解决了他们的消化体征或症状,并且在停止Notch抑制剂与所有胃肠体征和症状的解决之间的中值(范围)时间间隔为7天(4-24)。同样，停药和组织学异常消退之间的中位时间间隔为7天(1-10).阻断Notch信号诱导肠上皮的分泌细胞化生，进而导致短暂的腹泻。我们的结果证实了Notch信号在人类肠道稳态中的作用。
