gp130 as a novel therapeutic target in ovarian cancer

描述（由申请人提供）：糖蛋白130（gp 130）是八种细胞因子（IL 6、IL-11、IL-27、LIF、CNTF、OSM、CT-1和CLC）的受体信号传导复合物的中心。尽管gp 130位于该致癌信号网络的连接处，并且对于该网络的激活至关重要，但其作为上皮性卵巢癌（EOC）进展中的生物标志物的作用仍不清楚。此外，临床开发中没有gp 130的小分子抑制剂。验证gp 130作为EOC的生物标志物和分子靶点将有助于开发针对gp 130的药物，改善EOC治疗。最近，我们已经确定了一流的，有效的，安全的，口服活性的gp 130抑制剂。我们的初步研究表明，gp 130是必需的组成性激活的Stat 3在EOC细胞和支持细胞生长，增殖和生存。我们的主要gp 130抑制剂SC 144选择性抑制由gp 130配体（IL 6，LIF）诱导的下游信号通路的激活，对非gp 130配体（如IFN-γ，SDF-1α和PDGF）的激活无显著影响。SC 144在一组药物敏感性和耐药性EOC细胞中表现出细胞毒性，在人正常上皮细胞中没有显著毒性。在携带人EOC肿瘤的小鼠异种移植模型中，SC 144通过抑制gp 130和诱导肿瘤坏死显著抑制肿瘤生长。在正常组织中无明显毒性。据我们所知，SC 144是一流的强效口服小分子gp 130抑制剂。尽管IL 6在EOC中起重要作用，但尚不清楚gp 130是否可被视为预测标志物。更重要的是，尚未研究其在EOC亚型、癌症干细胞样细胞和耐药性中的信号通路的选择性抑制。我们研究的首要假设是，gp 130是一个重要的生物标志物，gp 130高表达或gp 130信号传导组成性活跃的患者预后和总生存率较差。我们进一步假设gp 130/Stat 3信号通路的抑制剂将有效地阻断EOC。为了确定gp 130作为EOC生物标志物的预后和预测重要性的意义，并评估其对患者样品来源的肿瘤生长的抑制作用，我们提出了以下目标。目的1：验证gp 130作为一个治疗靶点和一个新的生物标志物在一个大面板的EOC细胞系和患者组织。目标二：确定SC 144作为单药和与卡铂联合使用在来自初治和耐药患者的患者源性异种移植物模型中的体内疗效。目标3：阐明gp 130及其被SC 144抑制在EOC干细胞和耐药性中的作用，以及在我们的新的具有人肿瘤间质的小鼠EOC模型中的作用。

DESCRIPTION (provided by applicant): 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-γ, SDF-1α, 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 naïve 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.