Using Molecular Biology to Develop Drugs for Renal Cell Carcinoma

Abstract

BACKGROUND: Renal cell carcinoma is a disease marked by a unique biology which has governed it's long history of poor response to conventional cancer treatments. The discovery of the signaling pathway activated as a result of inappropriate constitutive activation of the hypoxia inducible factors (HIF), transcription factors physiologically and transiently stabilized in response to low oxygen, has provided a primary opportunity to devise treatment strategies to target this oncogenic pathway. OBJECTIVE: A review of the molecular pathogenesis of renal cell cancer as well as molecularly targeted therapies, both those currently available and those in development, will be provided. In addition, trials involving combination or sequential targeted therapy are discussed. METHODS: A detailed review of the literature describing the molecular biology of renal cell cancer and novel therapies was performed and summarized. RESULTS/CONCLUSION: Therapeutics targeting angiogenesis have provided the first class of agents which provide clinical benefit in a large majority of patients and heralded renal cell carcinoma as a solid tumor paradigm for the development of novel therapeutics. Multiple strategies targeting this pathway and now other identified pathways in renal cell carcinoma provide numerous potential opportunities to make major improvements in treating this historically devastating cancer.

Figure 1

Molecular Biology of Renal Cell Cancer and Its Association with the Hypoxia Pathway. Hypoxia inducible factor (HIF) synthesis is upregulated by growth factor signaling via the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. The mammalian target of rapamycin (mTOR) is an important regulator of the PI3K pathway. The Von Hippel-Lindau (VHL)/E3 ubiquitin ligase targets HIF for degradation in normoxic conditions. In hypoxic conditions or in absence of functional pVHL activity, HIF transcriptional activation results in target gene activation causing the angiogenic, proliferative, glycolytic phenotype of renal cell cancer.

Figure 2

Sites of Action of New Molecularly Targeted Therapies. Therapeutic compounds discussed in this review are depicted where they intersect with known RCC signaling pathways. mTOR mammalian target of rapamycin, MAP mitogen-activated protein, HIF hypoxia inducible transcription factor, VHL Von Hippel-Lindau gene, wt VHL wild type Von Hippel-Lindau gene, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, PDGF platelet derived growth factor, PDGFR platelet derived growth factor receptor, TGF-α transforming growth factor alpha, EGFR epidermal growth factor receptor, CA-IX carbonic anhydrase IX.