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

• 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
• 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

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(申请人提供)：美国每年大约有50,000例新的肾癌病例，导致10,000人死亡。如果及早发现，肾癌有可能通过手术治愈，然而，大约三分之一的晚期患者和三分之一的局部疾病患者在肾切除后发生转移。转移性肾癌患者的中位生存期为7-11个月，仅有10%的患者存活5年。显然，需要更有效的治疗方法。本研究描述了一种新的靶向MIF/DDT生长因子信号通路的方法，该信号通路针对最常见的肾癌--透明细胞肾细胞癌(CcRCC)。我们观察到同系物MIF(巨噬细胞移动抑制因子)和DDT(D-DOPAChrome互变酶)在绝大多数肾细胞癌患者样本中的表达，并发现它们的表达中断对肾细胞癌细胞的致瘤能力有显著影响。为了同时有效地靶向这两种配体，我们建议开发一种来自CD74的可溶性受体分子，CD74是MIF和DDT的天然受体之一。用可溶性受体抑制MIF和DDT有望同时干扰MIF和DDT，无论它们结合的是哪种受体，这比现有的方法包括小分子和抗体具有优势。目前，小分子只能干扰MIF信号，而不能干扰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将是治疗肾细胞癌的有效途径。其具体目的是：1)制备和纯化可溶性CD74受体分子，并在体外检测其抑制功能；2)创建腺病毒介导的可溶性CD74受体分子，用于治疗肾癌的动物模型。这项研究的设计基于CD74的一个已知的胞外结构域，它能够结合MIF和DDT，并使用一种已建立的体内方法来产生持续的、系统性的可溶性受体，以最佳地抑制信号网络。长期目标 目的是建立MIF/DDT通路作为治疗干预的可行靶点，并描述一种使用可溶性非外来生物制剂进行干预的有效方法。