gp130 as a novel therapeutic target in ovarian cancer

gp130作为卵巢癌的新治疗靶点

• 批准号: 8994723
• 负责人: NOURI NEAMATI
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994723
• 关键词: Antibodies; Biological Markers; CLC Gene; CTF1 gene; Cancer Cell Growth; Cancer Model; Cancer Prognosis; Cancer cell line; Carboplatin; Cell Line; Cell Survival; Cells; Ciliary Neurotrophic Factor; Clinic; Clinical; Collaborations; Complex; Cytokine Receptors; Development; Doxycycline; Drug resistance; Drug-sensitive; Endothelial Cells; Epithelial; Epithelial Cells; Epithelial ovarian cancer; Exhibits; Freezing; Growth; Health; Human; IL6 gene; In Vitro; Interferon Type II; Interferons; Interleukin-11; Knock-in; LIF gene; Lead; Ligand Binding; Ligands; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of ovary; Molecular Probes; Molecular Target; Mus; Necrosis Induction; Neoplasm Metastasis; Normal tissue morphology; Oncogenic; Outcome; Ovarian; PI3K/AKT; Pathway interactions; Patients; Phase II Clinical Trials; Platelet-Derived Growth Factor; Population; Positioning Attribute; Reagent; Receptor Signaling; Resistance; Role; STAT3 gene; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Solid; Stat3 Signaling Pathway; Stromal Cell-Derived Factor 1; Supporting Cell; Therapeutic; Tissue Microarray; Tissues; Toxic effect; Translations; Tumor Tissue; Validation; Xenograft Model; aldehyde dehydrogenases; angiogenesis; autocrine; cancer cell; cancer stem cell; cancer subtypes; cancer therapy; cell growth; cytokine; cytotoxicity; glycoprotein 130; improved; in vivo; inhibitor/antagonist; knock-down; new therapeutic target; novel; novel marker; outcome forecast; patient biomarkers; predictive marker; prognostic significance; response; small molecule; small molecule inhibitor; stem; survivin; targeted agent; therapeutic target; treatment response; tumor; tumor growth; tumor progression

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.

描述（由应用程序提供）：糖蛋白130（GP130）是八种细胞因子（IL6，IL-11，IL-27，IL-27，LIF，CNTF，CNTF，CNTF，OSM，CT-1和CLC）的接收器信号复合物的枢纽。尽管GP130位于该致癌信号网络的连接处，对于激活网络至关重要，但其作为上皮卵巢癌（EOC）进展的生物标志物的作用尚不清楚。此外，在临床发育下，GP130没有小分子抑制剂。在EOC中，GP130作为生物标志物和分子靶标的验证将促进靶向GP130靶向剂的发展并改善EOC治疗。最近，我们确定了GP130的一流，有效，安全和口服活跃的抑制剂。我们的初步研究表明，GP130对于EOC细胞中STAT3的组成型激活至关重要，并支持细胞的生长，增殖和存活。我们的铅GP130抑制剂SC144有选择地抑制了由GP130配体（IL6，LIF）诱导的下游信号通路的激活，对非GP130配体的激活，例如IFN-γ，SDF-1α和PDGF，对非GP130配体的激活没有显着影响。 SC144在一组药物敏感和耐药的EOC细胞中表现出细胞毒性，对人正常上皮细胞没有显着毒性。在带有人EOC肿瘤的小鼠异种移植模型中，SC144通过GP130抑制和诱导肿瘤中坏死的肿瘤生长显着抑制。正常组织中没有证据表明毒性。据我们所知，SC144是第一类潜力和口服的小分子GP130抑制剂。尽管IL6在EOC中起着重要作用，但尚不清楚GP130是否可以被视为预测标记。更重要的是，在EOC亚型，癌症干细胞和耐药性中，选择性抑制其信号传导途径尚未被研究。我们研究的总体假设是GP130是一个重要的生物标志物，并且具有高表达GP130或组成性活性GP130信号的患者的预后和总体存活率较差。我们进一步假设GP130/STAT3信号通路的抑制剂将有效阻止EOC。为了确定预后目标1：验证GP130作为EOC中的生物标志物，并评估其抑制对患者样品衍生肿瘤生长的影响，我们提出以下目的。目标1：在大型EOC细胞系和患者组织中验证GP130作为治疗靶标和新型生物标志物。 AIM 2：确定SC144的体内效率，作为单一药物，并与来自幼稚和耐药患者的患者衍生异种移植物模型中的卡泊蛋白结合使用。目标3：为了阐明SC144在EOC干细胞和耐药性中以及我们具有人类肿瘤基质的新型鼠EOC模型中，SC144抑制GP130及其抑制作用。