Groeneweg Jolijn W, Foster Rosemary, Growdon Whitfield B, Verheijen René H M, Rueda Bo R
Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
J Ovarian Res. 2014 Nov 4;7:95. doi: 10.1186/s13048-014-0095-1.
Ovarian cancer is the most lethal of all gynecologic malignancies because women commonly present with advanced stage disease and develop chemotherapy refractory tumors. While cytoreductive surgery followed by platinum based chemotherapy are initially effective, ovarian tumors have a high propensity to recur highlighting the distinct need for novel therapeutics to improve outcomes for affected women. The Notch signaling pathway plays an established role in embryologic development and deregulation of this signaling cascade has been linked to many cancers. Recent genomic profiling of serous ovarian carcinoma revealed that Notch pathway alterations are among the most prevalent detected genomic changes. A growing body of scientific literature has confirmed heightened Notch signaling activity in ovarian carcinoma, and has utilized in vitro and in vivo models to suggest that targeting this pathway with gamma secretase inhibitors (GSIs) leads to anti-tumor effects. While it is currently unknown if Notch pathway inhibition can offer clinical benefit to women with ovarian cancer, several GSIs are currently in phase I and II trials across many disease sites including ovary. This review will provide background on Notch pathway function and will focus on the pre-clinical literature that links altered Notch signaling to ovarian cancer progression.
卵巢癌是所有妇科恶性肿瘤中致死率最高的，因为女性通常在疾病晚期才出现症状，并且会发展出对化疗耐药的肿瘤。虽然减瘤手术联合铂类化疗最初是有效的，但卵巢肿瘤极易复发，这凸显了对新型疗法的迫切需求，以改善患病女性的治疗效果。Notch信号通路在胚胎发育中发挥着既定作用，该信号级联的失调与许多癌症有关。最近对浆液性卵巢癌的基因组分析表明，Notch通路改变是检测到的最普遍的基因组变化之一。越来越多的科学文献证实卵巢癌中Notch信号活性增强，并利用体外和体内模型表明用γ-分泌酶抑制剂（GSIs）靶向该通路可产生抗肿瘤作用。虽然目前尚不清楚Notch通路抑制是否能为卵巢癌女性带来临床益处，但目前有几种GSIs正在包括卵巢在内的许多疾病部位进行I期和II期试验。本综述将提供Notch通路功能的背景知识，并将重点关注将Notch信号改变与卵巢癌进展联系起来的临床前文献。
