gp130 as a novel therapeutic target in ovarian cancer

gp130作为卵巢癌的新治疗靶点

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：糖蛋白 130 (gp130) 是八种细胞因子（IL6、IL-11、IL-27、LIF、CNTF、OSM、CT-1 和 CLC）受体信号复合物的枢纽。位于该致癌信号网络的交界处，对于该网络的激活至关重要，其作为上皮性卵巢癌生物标志物的作用此外，目前尚无正在临床开发的 gp130 小分子抑制剂，验证 gp130 作为 EOC 的生物标志物和分子靶标将有助于 gp130 靶向药物的开发并改善 EOC 治疗。我们的初步研究表明，gp130 对于 gp130 的组成型激活至关重要。 EOC 细胞中的 Stat3 支持细胞生长、增殖和存活。我们的主要 gp130 抑制剂 SC144 选择性抑制 gp130 配体（IL6、LIF）诱导的下游信号通路的激活，对非 gp130 的激活没有显着影响。配体，例如 IFN-γ、SDF-1α 和 SC144 在一组药物敏感和耐药的 EOC 细胞中表现出细胞毒性，但没有显着影响。在携带人 EOC 肿瘤的小鼠异种移植模型中，SC144 通过抑制 gp130 并诱导肿瘤坏死而显着抑制肿瘤生长，据我们所知，SC144 在正常组织中没有明显的毒性。同类有效的口服活性小分子 gp130 抑制剂尽管 IL6 在 EOC 中发挥着重要作用，但尚不清楚 gp130 是否可以被视为预测标志物。值得注意的是，尚未研究其信号通路在 EOC 亚型、癌症干细胞样细胞和耐药性中的选择性抑制。我们研究的总体假设是 gp130 是一种重要的生物标志物，并且 gp130 高表达或持续活跃的患者。 gp130 信号通路的预后和总体生存率较差，我们进一步发现 gp130/Stat3 信号通路的抑制剂将有效阻断 EOC 的预后和预测重要性。 gp130 作为 EOC 的生物标志物，并评估其对患者样本来源的肿瘤生长的抑制作用，我们提出以下目标 1：验证 gp130 作为治疗靶点和在大量 EOC 细胞系中的新型生物标志物。目标 2：确定 SC144 作为单一药物以及与卡铂联合治疗来自初治患者和耐药患者的异种移植模型的体内疗效。阐明 gp130 及其在 EOC 干细胞和耐药性中的作用以及 SC144 对其的抑制作用，以及在我们的具有人肿瘤基质的新型小鼠 EOC 模型中的作用。