A novel soluble receptor-based therapy for Kidney Cancer

一种基于可溶性受体的新型肾癌疗法

基本信息

批准号：
8751723
负责人：
Scott Michael Welford
金额：
$ 17.24万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8751723
关键词：
Adverse effects Affect Amino Acids Animal Model Animals Antibodies Binding Biochemical Blood Circulation Blood Vessels CD44 gene CXCR4 gene Cell Proliferation Cells Cessation of life Chemotactic Factors Clear Cell Complement Factor D Data Disease Dopachrome isomerase Event Extracellular Domain Genetic Goals Growth Growth Factor Homologous Gene Human Hypoxia Hypoxia Inducible Factor IL8RB gene IgG2 Immunocompromised Host Immunoglobulins Immunosuppression In Vitro Individual Inflammatory Interruption Kidney Neoplasms Life Ligands Malignant Epithelial Cell Measures Mediating Migration Inhibitory Factor Modality Modeling Monoclonal Antibodies Mus Mutation Myelogenous Neoplasm Metastasis Nephrectomy Operative Surgical Procedures Output Pathway interactions Patients Porifera Production Proteins Publishing Regulation Regulatory T-Lymphocyte Renal Cell Carcinoma Renal carcinoma Research Design Role Sampling Shapes Signal Pathway Signal Transduction Stress Suppressor-Effector T-Lymphocytes System Testing Therapeutic Therapeutic Intervention Time Transcriptional Regulation Tumor Suppressor Genes Tumor Suppressor Proteins United States Vascular Endothelial Cell Virus adenoviral-mediated advanced disease angiogenesis bHLH-PAS factor HLF base cancer therapy conventional therapy cytokine design effective therapy gene delivery system in vivo macrophage macrophage migration inhibitory factor receptor migration neoplastic cell novel novel strategies novel therapeutics phenylpyruvate tautomerase prevent programs public health relevance receptor receptor binding receptor-mediated signaling response small molecule tumor tumor growth tumor microenvironment tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): There are roughly 50,000 new cases of renal cell carcinoma each year in the United States, leading to 10,000 deaths. If detected early, renal cancer is potentially curable by surgery, however about one third of the patients present with advanced disease, and a further one third of patients with local disease develop metastasis after nephrectomy. The median survival time of patients with metastatic renal cancer is 7-11 months, with only 10% of patients living 5 years. There is a clear need for more effective treatments. The present study describes a novel approach to target the MIF/DDT growth factor signaling pathway in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). We have observed expression of the homologues MIF (macrophage migration inhibitory factor) and DDT (D-dopachrome tautomerase) in the vast majority of ccRCC patient samples, and found that interruption of their expressions has dramatic effects on tumorigenic capacity of ccRCC cells. To effectively target both ligands simultaneously, we propose to develop a soluble receptor molecule derived from CD74, one of the natural receptors for both MIF and DDT. Inhibition with a soluble receptor holds promise to interfere with both MIF and DDT, regardless of which receptor they bind, offering advantages over existing modalities including small molecules and antibodies. Currently, small molecules can interfere with only MIF signaling, not DDT; and antibodies can only target either MIF or DDT, or a single receptor. The hypothesis is that dual inhibition of MIF and DDT via soluble a CD74 receptor will be an effective approach to treat ccRCC. The specific aims are to: 1) Create and purify a soluble CD74 receptor molecule, and test the inhibitory functions in vitro; and 2) Create an adenoviral-mediated soluble CD74 receptor molecule for treatment of renal cancer in an animal model. The study design is based on a known extracellular domain of CD74 that is capable of binding both MIF and DDT, and uses an established in vivo approach to produce sustained, systemic production of the soluble receptor for optimal inhibition of signaling networks. The long term goal is to establish the MIF/DDT pathway as a viable target for therapeutic intervention, and to describe an effective means to intervene using a soluble non-foreign biologic agent.

描述（由申请人提供）：美国每年大约有 50,000 例新发肾细胞癌病例，导致 10,000 人死亡。如果及早发现，肾癌可能可以通过手术治愈，但约三分之一的患者已处于晚期疾病，另外三分之一的局部疾病患者在肾切除术后出现转移。转移性肾癌患者的中位生存时间为7-11个月，只有10%的患者能活5年。显然需要更有效的治疗方法。本研究描述了一种针对最常见肾癌形式——透明细胞肾细胞癌 (ccRCC) 中 MIF/DDT 生长因子信号通路的新方法。我们在绝大多数 ccRCC 患者样本中观察到同源物 MIF（巨噬细胞迁移抑制因子）和 DDT（D-多巴色素互变异构酶）的表达，并发现其表达的中断对 ccRCC 细胞的致瘤能力具有显着影响。为了同时有效地靶向两种配体，我们建议开发一种源自 CD74 的可溶性受体分子，CD74 是 MIF 和 DDT 的天然受体之一。可溶性受体的抑制有望干扰 MIF 和 DDT，无论它们结合哪种受体，与包括小分子和抗体在内的现有方式相比具有优势。目前，小分子只能干扰MIF信号传导，不能干扰DDT；抗体只能针对 MIF 或 DDT，或单一受体。假设通过可溶性 CD74 受体双重抑制 MIF 和 DDT 将是治疗 ccRCC 的有效方法。具体目标是： 1）构建并纯化可溶性CD74受体分子，并进行体外抑制功能测试； 2) 创建腺病毒介导的可溶性 CD74 受体分子，用于治疗动物模型中的肾癌。该研究设计基于已知的 CD74 胞外结构域，该结构域能够结合 MIF 和 DDT，并使用已建立的体内方法持续、系统地产生可溶性受体，以实现信号网络的最佳抑制。长期目标目标是建立 MIF/DDT 途径作为治疗干预的可行目标，并描述使用可溶性非外来生物制剂进行干预的有效手段。