gp130 as a novel therapeutic target in ovarian cancer

描述(申请人提供)：糖蛋白130(Gp130)是八种细胞因子(IL-6、IL-11、IL-27、LIF、CNTF、OSM、CT-1和CLC)的受体信号复合体的中枢。尽管gp130位于该致癌信号网络的交界处，并且对于该网络的激活是必不可少的，但其作为上皮性卵巢癌(EOC)进展的生物标志物的作用仍不清楚。此外，目前还没有gp130的小分子抑制剂处于临床开发阶段。证实gp130是卵巢癌的生物标志物和分子靶点，将促进gp130靶向药物的开发，提高卵巢癌的治疗水平。最近，我们已经发现了一流的、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在EOC细胞中对STAT3的结构性激活是必不可少的，并支持细胞的生长、增殖和存活。我们的先导gp130抑制剂SC144选择性地抑制gp130配体(IL 6、LIF)诱导的下游信号通路的激活，而对非gp130配体如干扰素-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细胞上显示出细胞毒性，而在人类正常上皮细胞中没有明显的毒性。在荷人卵巢癌小鼠移植瘤模型中，SC144通过抑制gp130和诱导肿瘤坏死而显著抑制肿瘤生长。在正常组织中未见明显毒性。据我们所知，SC144是一种一流的有效的口服活性小分子gp130抑制剂。尽管IL6在EoC中起着重要作用，但目前尚不清楚gp130是否可以被认为是一个预测标记物。更重要的是，对其信号通路在EOC亚型、肿瘤干细胞样细胞和耐药中的选择性抑制还没有研究。我们研究的主要假设是gp130是一个重要的生物标志物，gp130高表达或gp130信号活性高的患者预后和总存活率较差。我们进一步假设gp130/STAT3信号通路的抑制剂将有效地阻断EOC。为了确定gp130作为卵巢癌生物标记物的预后和预测重要性，并评估其抑制患者样本来源的肿瘤生长的效果，我们提出了以下目标。目的1：在大量卵巢癌细胞系和患者组织中验证gp130作为治疗靶点和新的生物标志物的有效性。目的：研究SC144作为单一药物以及与卡铂联合应用对单纯和耐药患者的异种移植模型的体内疗效。目的：探讨gp130在卵巢癌细胞及其耐药中的作用和SC144对其的抑制作用，以及我们建立的人肿瘤间质卵巢癌新模型。

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.