Glycoprotein 130 (gp130) is a hub for a receptor-signaling complex for eight cytokines (IL6, IL-11, IL-27, LIF, CNTF, OSM, CT-1 and CLC). Although gp130 is positioned at the junction of this oncogenic signaling network and is essential for activation of the network, its role as a biomarker in epithelial ovarian cancer (EOC) progression remains unclear. Furthermore, there are no small-molecule inhibitors of gp130 under clinical development. Validation of gp130 as a biomarker and molecular target in EOC will facilitate the development of gp130-targeting agents and improve EOC therapy. Recently, we have identified first-in-class, efficacious, safe, and orally active inhibitors of gp130. Our preliminary study shows that gp130 is essential for the constitutive activation of Stat3 in EOC cells and supports cell growth, proliferation, and survival. Our lead gp130 inhibitor, SC144, selectively inhibits the activation of downstream signaling pathways induced by gp130 ligands (IL6, LIF), with no significant effects on the activation by non-gp130 ligands, such as IFN-?, SDF-1?, and PDGF. SC144 exhibits cytotoxicity in a panel of drug-sensitive and -resistant EOC cells, with no significant toxicity in human normal epithelial cells. In a mouse xenograft model bearing human EOC tumors, SC144 significantly inhibited tumor growth through gp130 inhibition and induction of necrosis in the tumor. No toxicity was evident in normal tissues. To our knowledge, SC144 is the first-in-class potent and orally active small-molecule gp130 inhibitor. Despite the important role of IL6 in EOC, it is unclear if gp130 can be considered a predictive marker. More significantly, selective inhibition of its signaling pathway in EOC subtypes, cancer stem-like cells, and drug resistance has not been studied. The overarching hypothesis of our study is that gp130 is an important biomarker and that patients with high expression of gp130 or constitutively active gp130 signaling will have poor prognosis and overall survival. We further hypothesize that inhibitors of gp130/Stat3 signaling pathway will effectively block EOC. To determine the significance of prognostic and predictive importance of gp130 as a biomarker in EOC, and assess the effect of its inhibition on patient sample derived tumor growth, we propose the following aims.
Aim 1 : To validate gp130 as a therapeutic target and a novel biomarker in a large panel of EOC cell lines and patient tissues.
Aim 2 : To determine in vivo efficacy of SC144, as a single agent and in combination with carboplatin in patient-derived xenografts models from na?ve and drug-resistant patients.
Aim 3 : To elucidate the role of gp130 and its inhibition by SC144 in EOC stem cells and drug resistance and in our novel murine EOC model with human tumor stroma.
Recently, we have identified first-in-class, efficacious, safe, and orally active inhibitors of gp130. We are using these agents as molecular probes to understand the mechanistic significance and therapeutic potential of targeting gp130 in ovarian cancer.
