The von Hippel-Lindau tumor suppressor protein and kidney cancer

Inactivation of the von Hippel-Lindau tumor suppressor gene (VHL) plays a causal role in the development of hereditary (von Hippel-Lindau disease) and sporadic clear cell carcinoma of the kidney. The VHL gene product, pVHL, is the substrate recognition subunit of a ubiquitin ligase that targets the alpha subunits of the heterodimeric transcription factor HIF (Hypoxia-inducible Factor) for destruction when oxygen is present. Cells lacking functional pVHL, or exposed to low oxygen (hypoxia), accumulate HIF, which activates a suite of genes involved in acute or chronic adaptation to hypoxia. A number of these genes, including VEGF, PDGF B, and TGF?, have been implicated in tumorigenesis. Downregulation of HIF is both necessary and sufficient for pVHL to suppress the growth of VHL-/- tumor cells in animal models, suggesting that drugs that inhibit HIF, or HIF-responsive gene products, might be useful for the treatment of clear cell kidney cancer. Indeed, multiple drugs that inhibit VEGF or its receptor KDR have now demonstrated activity against this disease. The rate of HIF transcription and synthesis is sensitive to changes in the activity of the PI3K-AKT-mTOR pathway. A recent randomized trial showed that patients with kidney cancer benefited from treatment with an mTOR inhibitor. Current studies are aimed at combining VEGF inhibitors with mTOR inhibitors as well as at identifying additional agents that can, at least indirectly, inhibit HIF or cancer-relevant HIF-responsive gene products.