Hereditary kidney cancer: unique opportunity for disease-based therapy

Abstract

Kidney cancer is not a single disease; it is comprised of several different types of cancer, each with a different histology, with a different clinical course, caused by a different gene, and responding differently to therapy. The VHL gene is the gene for the hereditary cancer syndrome, von Hippel-Lindau, as well as for the common form of sporadic, noninherited, clear cell kidney cancer. Understanding the VHL-hypoxia inducible factor (HIF) pathway has provided the foundation for the development of several agents targeting this pathway, such as sunitinib, sorafenib, and temsirolimus. Hereditary papillary renal carcinoma (HPRC) is a hereditary renal cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal, type 1 papillary renal cell carcinoma. The genetic defect underlying HPRC is MET, the cell surface receptor for hepatocyte growth factor. Mutations of MET also have been identified in a subset of tumors from patients with sporadic type 1 papillary renal cell carcinoma (RCC). Clinical trials targeting the MET pathway are currently underway in patients with HPRC and in patients with sporadic (nonhereditary) papillary kidney cancer. The BHD gene (also known as folliculin or FLCN) is the gene for Birt-Hogg-Dube syndrome, an autosomal-dominant genodermatosis associated with a hereditary form of chromophobe and oncocytic, hybrid RCC. Preclinical studies are underway targeting the BHD gene pathway in preparation for clinical trials in Birt-Hogg-Dube and sporadic chromophobe RCC. Patients with hereditary leiomyomatosis RCC (HLRCC) are at risk for developing cutaneous and uterine leiomyomas and a very aggressive type of RCC. HLRCC is characterized by germline mutation of the Krebs cycle enzyme, fumarate hydratase (FH). Studies of the tricarboxylic acid cycle and the VHL-HIF pathways have provided the foundation for therapeutic approaches in patients with HLRCC-associated kidney cancer as well as other hereditary and sporadic forms of RCC.

Figure 1

Kidney cancer is made up of a number of different types of cancer, each with a different histologic type, with a different clinical course, responding differently to therapy and caused by different genes. The VHL gene is the gene for von Hippel-Lindau and for sporadic clear cell kidney cancer. The MET gene is the gene for Hereditary Papillary Renal Cell Carcinoma (HPRC) and has been found to be mutated in a subset of type 1 papillary renal tumors (13%).(37) The fumarate hydratase gene is the gene for hereditary leiomyomatosis renal cell carcinoma (HLRCC); the genetic basis of sporadic, type 2 papillary kidney cancer remains to be determined. The BHD gene is the gene for the hereditary form of chromophobe kidney cancer and oncocytoma associated with Birt Hogg-Dubé. BHD gene mutations have been identified in sporadic chromophobe kidney cancer,(67) however, the primary genetic basis of sporadic chromophobe kidney cancer and oncocytomas remains to be determined. Adapted from Linehan, et al.(5)

Figure 2

The VHL gene is the gene for clear cell kidney cancer. The VHL protein targets hypoxia-inducible factor (HIF) for ubiquitin-mediated degradation. When the VHL gene is mutated in clear cell kidney cancer, the VHL protein cannot target and degrade HIF. HIF over-accumulates and causes increased transcription of downstream genes such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) (A). Current therapeutic approaches include antibodies such as bevacizumab, which target VEGF, as well as agents such as sunitinib and sorafenib, which target the VEGF and PDGF receptors.(C) Future approaches could include agents which target HIF directly.(B) From Linehan, et al.(5)