A novel soluble receptor-based therapy for Kidney Cancer

描述（由申请人提供）：在美国，每年大约有50,000例新的肾细胞癌病例，导致10,000例死亡。如果早期发现，肾癌有可能通过手术治愈，但约三分之一的患者病情进展到晚期，另有三分之一的局部疾病患者在肾切除术后发生转移。转移性肾癌患者的中位生存时间为7-11个月，只有10%的患者存活5年。显然需要更有效的治疗方法。本研究描述了一种在最常见的肾癌透明细胞肾细胞癌（ccRCC）中靶向MIF/DDT生长因子信号通路的新方法。我们观察了巨噬细胞迁移抑制因子（macrophage migration inhibitory factor， MIF）和D-dopachrome tautomerase， DDT （D-dopachrome tautomerase， DDT）的同源物在绝大多数ccRCC患者样本中的表达，发现中断它们的表达对ccRCC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。不管MIF和DDT结合的是哪种受体，用可溶性受体抑制它们都有望干扰它们，这比现有的方式（包括小分子和抗体）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ccRCC的有效方法。具体目的是：1)建立和纯化可溶性CD74受体分子，并在体外测试其抑制功能；2)在动物模型中构建腺病毒介导的可溶性CD74受体分子用于治疗肾癌。该研究设计基于已知的CD74细胞外结构域，该结构域能够结合MIF和DDT，并使用一种已建立的体内方法来产生持续的、系统的可溶性受体，以最佳地抑制信号网络。长期目标

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.