DF/HCC Program Affiliation

Translational Pharmacology and Early Therapeutic Trials
Angiogenesis, Invasion and Metastasis
Cutaneous Oncology and Melanoma

Research Abstract

Renal cancer, angiogenesis, and gene therapy

Recent studies focus on the mechanism of action of the von Hippel-Lindau (VHL) tumor suppressor gene, mutations in which occur in the majority of adult renal carcinoma cases. The laboratory has identified both gene and protein targets for the VHL gene product. Three physiologically interesting candidates - TGF-a, TGF-b, and VEGF - have been discovered. Inhibition of renal tumor growth can be elicited by treatment with anti-TGF-b antibodies, with the major mechanism being an anti-angiogenic one.

A major program in characterizing the mechanism of action of the anti-angiogenic proteins, endostatin, angiostatin, and kringle 5. In addition, the laboratory has discovered that a fragment of collagen XV that has a 60 percent homology to endostatin has anti-angiogenic properties. Structure-function analysis of this fragment suggests that a smaller internal region has enhanced anti-angiogenic activity.

Finally, approaches to delivering genes into the kidney are being explored as a way of creating disease models, studying cis regulatory elements in vivo, and for potential human therapy. The focus is on adenovirus vectors, since the laboratory has discovered that by cooling the kidney and using vasodilators, kidney vasculature can be transduced without significant morphologic damage to the kidney. The clinical focus is on genetically engineering the kidney with immunosuppressive genes at the time of transplantation (collaboration with T. Strom and T. Libermann) and on the delivery of differentiation factors that act in a paracrine manner to reduce fibrosis in a model of chronic renal disease.

Publications

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