Kidney Cancer Research

We have studied cancer of the kidney for nearly 20 years, in collaboration with many scientists and medical centers across the United States and worldwide. July 1, 2002 started my twenty- first year at the NCI. Our approach has been predicated on the thesis that understanding the fundamental basis of kidney cancer may lead to better methods for treatment of that disease.¹

In our initial work in the search for the gene(s) for clear cell kidney cancer we identified an area of abnormality in tumor tissue from patients with kidney cancer, a loss of a segment of chromosome 3 in tumor tissue from patients with clear cell renal carcinoma.² We did further mapping studies in this region and narrowed the region of a potential kidney cancer tumor suppressor gene on chromosome 3.³ However, this region was too big to search for a disease gene by conventional methods, so we initiated study of an inherited form of renal cell carcinoma, von Hippel-Lindau.

Inherited forms of RCC: VHL

We set up a program at the NCI to evaluate patients with inherited forms of renal carcinoma in order to identify those genes. In our initial work on VHL we confirmed and further refined previous mapping to a location on the short arm of chromosome 3. In the Spring of 1993 we reported the identification of the VHL gene.⁴ Although it was not a "given" that this would be the gene we had looked for for so long, we next evaluated tumors from patients with the common form of non-inherited kidney cancer, clear cell renal carcinoma, to see if there would be mutations of the VHL gene in these tumors. We found a high percentage of tumors from patients with clear cell renal carcinoma to have mutation of the VHL gene.⁵

We next set out to understand the VHL gene, how damage to this gene leads to cancer. The hope was – and still is — to identify small molecules that would interrupt this sequence of events – this pathway — as a potential therapy for patients with clear cell renal carcinoma. In our initial studies we identified proteins that bind to VHL (elongins c and b and Cul-2).6,7 We now know that the VHL protein forms a complex with these and other proteins to target two proteins called HIF1 alpha and HIF2 alpha for degradation, effectively turning off production of these proteins. When there is a mutation of the VHL gene, and it is inactivated, it can no longer target HIF for degradation. This allows an over-accumulation of HIF, which in turn leads to the over production of a number of proteins known to be important in cancer, such as VEGF (angiogenesis), TGF alpha (unregulated growth of the cancer), PDGF (unregulated growth of the cancer) and Glut1 (transport of glucose from the host into the cancer cells).

VHL kidney cancer pathway

We are currently working on understanding the effect of HIF over accumulation in the formation of kidney cancer. We feel that this pathway provides unique opportunities for molecular targeting of kidney cancer.

Many diseases

Kidney cancer is not "one disease", it represents many types of cancer that occur in this organ. Each different type of kidney cancer is characterized by a different histologic pattern, is caused by a different gene, has a different clinical course and may respond differently to therapy. In addition to VHL we are studying other forms of hereditary and non-hereditary kidney cancer. It is our feeling that understanding the genetic basis of these cancers will provide attractive targets for molecular therapeutics – drug therapies that could reverse or prevent tumor growth. The strategy that we have been pursuing for nearly two decades has been shown to be effective in patients with a form of gastric cancer. (STI-571/Gleevec, CML/GIST tumors). We view this as "proof of principle" for such an effort.

These molecular therapeutic strategies are not separate from the efforts being pursued to develop immunologic therapies and/or vaccine strategies for renal cell carcinoma. They are synergistic strategies which are inextricably intertwined. One example of an approach aiming to prevent formation of new tumors targets one of the events downstream from VHL, manipulating the levels of VEGF. This has already been shown to be promising in patients treated by Yang and colleagues at the NCI. Other strategies involving VHL gene pathway targets are underway and we are encouraged by the progress to date.

The VHL Family Alliance has provided enormous benefit to both clinical as well as basic investigators in the field and, most importantly, to those patients with VHL and renal cell carcinoma that we all care for.

1. Linehan, W. M., Zbar, B., and Klausner, R. D. Renal Carcinoma. In B. Vogelstein and K. W. Kinzler (eds.), The Genetic Basis of Human Cancer, 2nd ed New York: McGraw-Hill 2002.

2. Zbar, B., Brauch, H., Talmadge, C., and Linehan, W. M. Loss of alleles ... renal cell carcinoma. Nature, 327: 721-724, 1987.

3. Anglard, P., Brauch, T. H., Weiss, G. H., Latif, F., Merino, M. J., Lerman, M. I., Zbar, B., and Linehan, W. M. Molecular analysis of genetic changes... Cancer Res, 51: 1071-1077, 1991.

4. Latif, F., et al.Identification of the von Hippel-Lindau disease tumor suppressor gene. Science, 260: 1317-1320, 1993.

5. Gnarra, J. R., et al., Mutation of the VHL tumour Suppressor Gene in Renal Carcinoma. Nat.Gen., 7: 85-90, 1994.