gp130 as a novel therapeutic target in ovarian cancer

描述（由申请人提供）：糖蛋白130 （gp130）是8种细胞因子（IL6, IL-11, IL-27， LIF， CNTF， OSM， CT-1和CLC）的受体信号复合物的枢纽。尽管gp130位于这一致癌信号网络的连接处，对网络的激活至关重要，但其在上皮性卵巢癌（EOC）进展中的生物标志物作用尚不清楚。此外，目前还没有gp130的小分子抑制剂处于临床开发阶段。gp130作为EOC的生物标志物和分子靶点的验证将促进gp130靶向药物的开发，并改善EOC的治疗。最近，我们已经确定了一流的、有效的、安全的、口服活性的gp130抑制剂。我们的初步研究表明，gp130对EOC细胞中Stat3的组成激活至关重要，并支持细胞生长、增殖和存活。我们的主要gp130抑制剂SC144选择性地抑制gp130配体（IL6， LIF）诱导的下游信号通路的激活，而对非gp130配体（如IFN-γ， SDF-1α和PDGF）的激活没有显著影响。SC144在一组药物敏感和耐药的EOC细胞中表现出细胞毒性，对人类正常上皮细胞无明显毒性。在携带人类EOC肿瘤的小鼠异种移植模型中，SC144通过gp130抑制和诱导肿瘤坏死显著抑制肿瘤生长。对正常组织无明显毒性。据我们所知，SC144是首个有效的口服小分子gp130抑制剂。尽管IL6在EOC中起着重要作用，但gp130是否可以作为预测标志物尚不清楚。更重要的是，其信号通路在EOC亚型、癌症干细胞样细胞和耐药中的选择性抑制尚未得到研究。本研究的主要假设是gp130是一种重要的生物标志物，gp130高表达或组成性gp130信号活跃的患者预后和总生存期较差。我们进一步假设gp130/Stat3信号通路抑制剂可以有效阻断EOC。为了确定gp130作为EOC生物标志物的预后和预测重要性，并评估其对患者样本源性肿瘤生长的抑制作用，我们提出以下目标。目的1：验证gp130作为EOC细胞系和患者组织的治疗靶点和新型生物标志物。目的2：确定SC144在naïve患者来源的异种移植模型和耐药患者中作为单药和与卡铂联合使用的体内疗效。目的3：阐明gp130及其被SC144抑制在EOC干细胞和耐药性中的作用，以及在我们的新型人肿瘤基质小鼠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.