Molecular diagnosis and therapy of kidney cancer

Abstract

Kidney cancer is not a single disease; it is made up of a number of cancers that occur in the kidney, each having a different histology, following a different clinical course, responding differently to therapy, and caused by a different gene. Study of the genes underlying kidney cancer has revealed that it is fundamentally a metabolic disorder. Understanding the genetic basis of cancer of the kidney has significant implications for diagnosis and management of this disease. VHL is the gene for clear cell kidney cancer. The VHL protein forms a complex that targets the hypoxia-inducible factors for ubiquitin-mediated degradation. Knowledge of this pathway provided the foundation for the development of novel therapeutic approaches now approved for treatment of this disease. MET is the gene for the hereditary form of type 1 papillary renal carcinoma and is mutated in a subset of sporadic type 1 papillary kidney cancers. Clinical trials are currently ongoing with agents targeting the tyrosine kinase domain of MET in sporadic and hereditary forms of papillary kidney cancer. BHD is the gene for the hereditary type of chromophobe kidney cancer. It is thought to be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. Hereditary leiomyomatosis renal cell carcinoma, a hereditary form of type 2 papillary renal carcinoma, is caused by inactivation of a Krebs cycle enzyme due to mutation. Knowledge of these kidney cancer gene pathways has enabled new approaches in the management of this disease and has provided the foundation for the development of targeted therapeutics.

Figure 1. Targeting the VHL gene pathway in clear cell kidney cancer

The VHL protein makes a complex with other proteins and targets hypoxia inducible factor for ubiquitin-mediated degradation. This is an oxygen-sensitive process; when the oxygen level is normoxic, the VHL complex targets HIF and degrades it. When there is hypoxia, HIF is not degraded and this causes the transcription of a number of genes known to be important in cancer, such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and transforming growth factor α (TGF-α). Knowledge of the VHL/HIF pathway provides the foundation for the development of novel therapeutic approaches to the treatment of patients with advanced kidney cancer. Five FDA approved agents, sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab are currently used in treatment of patients with advanced clear cell kidney cancer.(42) (Adapted from Pfaffenroth, et al.(60))

Figure 2. Targeting the MET gene pathway in type 1 papillary kidney cancer

Hereditary papillary renal carcinoma (HPRC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal type 1 papillary kidney cancer.(94) The gene for HPRC was found to be MET, the cell surface receptor for the ligand, hepatocyte growth factor. Activating mutations in the tyrosine kinase domain of MET are found in the germline of HPRC patients and in a subset of tumors from patients with sporadic type 1 papillary kidney cancer.(65, 66) In a multicenter Phase II trial, the dual MET/VEGFR2 kinase inhibitor, GSK'089, has shown activity in patients with papillary RCC, including those with MET mutation.(71) (Adapted from Linehan et al.(43))

Figure 3. Kidney cancer is fundamentally a metabolic disorder

The kidney cancer genes, VHL, MET, BHD, TSC1, TSC2, fumarate hydratase and succinate dehydrogenase, have in common that they are involved in energy, nutrient, iron and oxygen sensing. Targeting the metabolic defects in kidney cancer provides the potential for the development of more durable and effective forms of therapy for patients with this disorder.