Notch signaling in serous ovarian cancer

Abstract

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.

Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma

“…NOTCH signaling participates in TIC fate in gliomas (Fan et al, 2006) and lung cancer (Sullivan et al, 2010; Zheng et al, 2013). GSI inhibitors of NOTCH exhibit potent anti-tumor activity in glioma (Fan et al, 2010; Fan et al, 2006), lung (Konishi et al, 2007), and ovarian cancers (Groeneweg et al, 2014a; Groeneweg et al, 2014b) and the potent GSI PF-03084014 has shown clinical promise in advanced cancer patients (Messersmith et al, 2015). The anti-rheumatoid gold salts ATM and ANF selectively inhibit PKCι signaling and block growth of lung (Erdogan et al, 2006; Fields et al, 2007; Regala et al, 2008; Stallings-Mann et al, 2006), pancreatic (Butler et al, 2015; Scotti et al, 2012) and ovarian (Wang et al, 2013) tumors in vitro and in vivo , and two clinical studies have demonstrated proof-of-principle for PKCι inhibitor-based therapy with ATM (Mansfield et al, 2013) and ANF (Jatoi et al, 2014).…”

Galectin-3 supports stemness in ovarian cancer stem cells by activation of the Notch1 intracellular domain

“…Previously, it was reported that OVCAR3, SKOV3, and CaOV3 cells, as well as a large portion (76%) of human ovarian papillary serous adenocarcinomas, express NICD, which is a potential target for new drug therapies in ovarian cancer [25]. Notch signaling is also a potential diagnostic marker of epithelial ovarian cancer [26]. Up-regulation of the Notch3 and increased expression of the Jagged2 was reported in ovarian cancers [27, 28].…”

The role of Notch signaling in the mammalian ovary

“…Disruption of Notch signaling results in multiple human diseases including Alagille syndrome (Oda et al 1997), familial aortic valve disease (Garg et al 2005), Adams-Oliver syndrome (Stittrich et al 2014), Hajdu-Cheney syndrome (Simpson et al 2011), spondylocostal dysostosis (Bulman et al 2000), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Joutel et al 1996), Alzheimer disease (Kopan & Goate 2000), and cancers including T-cell acute lymphoblastic leukemia (Weng et al 2004) and pancreatic (Mullendore et al 2009), colon (Reedijk et al 2008), and ovarian cancers (Groeneweg et al 2014). …”

“…Alterations in the expression of Notch pathway genes has also been correlated with ovarian cancers that develop resistance to treatment (Groeneweg et al 2014); however, it is unclear by what means aberrant Notch signaling may facilitate the survival of cancer cells. Difficulty in treating ovarian tumors has at least in part been attributed to the formation or maintenance of cancer stem cells (Jordan et al 2006, Shah et al 2013, Walters Haygood et al 2014).…”

“…In a second study (Hu et al 2011), Dll4 was found to be upregulated in more than half of ovarian cancer samples that were analyzed, and increased levels of Dll4 expression were correlated with overall poor survival. New treatments designed to target the Notch pathway will hopefully provide additional means by which to counter the various mechanisms by which altered Notch signaling promotes the establishment and maintenance of tumors, especially those that are resistant to current therapeutic options (Rose 2009, Domingo-Domenech et al 2012, Sahebjam et al 2013, Groeneweg et al 2014). …”