The focus of my research group is understanding the genetic and molecular aberrations critical for the development of invasive renal cell carcinoma. Our approach utilizes genetically engineered murine embryonic stem (ES) cells expressing clinically important point mutations in the von Hippel-Lindau (VHL) tumor suppressor gene, which is mutated in over 70% of the most common form of renal cancer. These cell lines provide a tool for the in vitro study of cellular VHL activity in the absence of competing mutations as well as the ability to create a number of animal model systems for tumor growth and development.

VHL-mediated cancers occur as a result of dysregulation of the hypoxic response system. Under normal oxygen tension, VHL functions as a component of an E3 ubiquitin ligase, targeting a family of transcription factors (HIF, Hypoxia Inducible Factor) for degradation. In the absence of VHL, or when oxygen is limiting, HIF protein is stabilized and induces the expression of a large panel of hypoxic response genes including VEGF, flt-1, Glut-1, erythropoietin, carbonic anhydrases, endothelin-1, and the enzymes of glycolysis. Using our panel of ES cells expressing various mutant versions of VHL, we are able to investigate the effects of VHL on processes integral to tumorigenesis including angiogenesis, vasculogenesis, hypoxic response signaling, extracellular matrix remodeling, and cell cycle signaling. These genetically targeted cells additionally provide the platform for the generation of a series of VHL mutant mice as an in vivo model of the human disease. Our cell culture and mouse models provide excellent models for exploring the pathogenesis of renal cancer as well as serving as tools for drug development.

Clinically, my focus is the treatment of renal cell carcinoma. Very few agents have shown efficacy for patients with advanced stage disease. Using the information we are able to glean from the experimental models in the laboratory our goal is to provide innovative care to patients with renal cell carcinoma, and to use those models to support a program of drug discovery targeting this particular cancer. To that end, I oversee a clinical research program within the multidisciplinary genitourinary oncology group that offers biologically active treatment protocols to patients with renal cell carcinoma at all stages of disease.