Molecular Therapeutics of Kidney Cancer: VHL Gene and Fumarate Hydratase Gene

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

In 1997 we discovered the location of the clear cell kidney cancer gene. We showed that there was a consistent loss of the short arm of chromosome 3 in tumors from patients with clear cell renal cell carcinoma and predicated that this indicated the location of the ccRCC gene and that this gene would enable the cell to respond to environmental changes (Nature 1987). In 1993 we discovered the clear cell renal cell carcinoma gene and named it the VHL gene, the sixth human cancer gene identified (Science 1993). In 1994 we discovered VHL gene mutations in clear cell renal cell carcinoma and showed for the first time precision molecular genetic characterization of different types of kidney cancer. In 1995 we identified elongin C and elongin b and the critical binding proteins of VHL (Science 1995). In 1997 we make the critical breakthrough to find CUL2 and binding to the VHL complex (PNAS 1997). This showed, for the first time, that VHL is part of an E3 ubiquitin degradation complex. In 1996 we showed that the VHL gene regulates hypoxia-inducible genes and predicted that hypoxia-inducible factor (HIF) was the target of the VHL gene complex. This work was cited by the Nobel Assembly as the critical foundation for the discovery of the PHD2 VHL-HIF oxygen sensing pathway which was the basis of the 2019 Nobel Prize. In 2002 we identified HIF2 as the critical VHL-HIF RCC pathway. In 2016 we initiated clinical trials evaluating the role of a HIF2 inhibitor, belzutifan, in patients affected with VHL. We have seen dramatic responses in renal, pancreatic, CNS and retinal tumors, which has led to approval of this agent in 26 countries, including the United States and China. We continue to work on the development of even more effective combinations for patients affected with von Hippel Lindau as well as sporadic clear cell renal cell carcinoma. Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyomas and a very aggressive form of type 2 papillary kidney cancer. The gene for HLRCC is the Krebs cycle enzyme, fumarate hydratase. We have found mutations in the FH gene in ~95% of our HLRCC families. Studies are underway to determine how inactivation of a Krebs cycle enzyme can lead to kidney cancer and how we can target this pathway for treatment of HLRCC-associated kidney cancer as well as sporadic, non-inherited type 2 papillary kidney cancer.