New Strategies in Renal Cell Carcinoma: Targeting the Genetic and Metabolic Basis of Disease
- 1 January 2015
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 21 (1), 10-17
- https://doi.org/10.1158/1078-0432.ccr-13-2993
Abstract
The development of new forms of treatment of advanced renal cell carcinoma over the past two decades has been primarily focused on targeting the VHL/HIF pathway. The recent identification of mutations of chromatin-remodeling genes in clear-cell renal carcinoma (ccRCC), of genomic heterogeneity, and of a Warburg-like metabolic phenotype in advanced disease has had a profound effect on our understanding of the evolution of ccRCC and on potential approaches to personalized therapy. Early approaches to therapy for patients with advanced type I papillary RCC that have centered around the MET/HGF pathway will expand as more genomic information becomes available. Sporadic and familial type II papillary renal cell carcinoma are characterized by enhanced aerobic glycolysis and share an antioxidant response phenotype. In fumarate hydratase–deficient RCC, fumarate-induced succination of KEAP1 activates Nrf2 signaling. CUL3 and Nrf2 mutations as well as an Nrf2 activation phenotype are found in sporadic type II papillary RCC. Therapeutic approaches designed to target the Nrf2 pathway as well as to impair blood flow and glucose delivery in these cancers that are highly dependent on a robust tumor vasculature and on ready availability of glucose for energy production and glycolysis are in development. Clin Cancer Res; 21(1); 10–17. ©2015 AACR.Keywords
This publication has 73 references indexed in Scilit:
- Integrated molecular analysis of clear-cell renal cell carcinomaNature Genetics, 2013
- Reductive carboxylation supports growth in tumour cells with defective mitochondriaNature, 2011
- Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 SignalingCancer Cell, 2011
- The Glycolytic Shift in Fumarate-Hydratase-Deficient Kidney Cancer Lowers AMPK Levels, Increases Anabolic Propensities and Lowers Cellular Iron LevelsCancer Cell, 2011
- Identification and evaluation of soft coral diterpenes as inhibitors of HIF-2α induced gene expressionBioorganic & Medicinal Chemistry Letters, 2011
- Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinomaNature, 2011
- Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3Nature Genetics, 2010
- Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008International Journal of Cancer, 2010
- Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genesNature, 2010
- UOK 262 cell line, fumarate hydratase deficient (FH−/FH−) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancerCancer Genetics and Cytogenetics, 2010