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.
Clear cell renal cell carcinoma (ccRCC) is the most common form of renal cancer, and characterized by alterations in the VHL tumor suppressor gene. The purpose of the present study is to investigate a novel therapeutic strategy to treat patients with ccRCC using an endogenous biologic to block a critical growth and survival signaling pathway with minimal expected side effects.
|Du, Weinan; Zhang, Luchang; Brett-Morris, Adina et al. (2017) HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun 8:1769|
|Gupta, Yashi; Pasupuleti, Vinay; Du, Weinan et al. (2016) Macrophage Migration Inhibitory Factor Secretion Is Induced by Ionizing Radiation and Oxidative Stress in Cancer Cells. PLoS One 11:e0146482|