Update on targeted therapies for clear cell renal cell carcinoma

Abstract

Purpose of review: The article reviews the evolution of targeted therapies for clear cell renal cell carcinoma (RCC) and recent developments in the field. The vast majority of work in kidney cancer deals with clear cell RCC, which is the most common variant of this malignancy. The identification of loss of function of the von Hippel-Lindau protein as the basis for clear cell RCC, in addition to the well designed clinical trials that have ensued, provide an outstanding model for the development of mechanism-based targeted therapy in cancer.

Recent findings: The treatment of advanced and metastatic RCC continues to be a major challenge for uro-oncologists despite the approval of six targeted therapies over the past 5 years. This rapid growth in therapeutic options has brought much needed improvements in overall and progression-free survival, although durable complete responses are rare. However, the plurality of treatments also poses challenges in terms of selecting the best therapy for a given patient, designing trials with appropriate comparison arms and endpoints, identifying well tolerated and effective drug combinations or sequences, and determining the role of targeted therapies in the neoadjuvant and adjuvant settings.

Summary: Vascular endothelial growth factor and mammalian target of rapamycin-targeted therapies continue to play a critical role in the management of advanced and metastatic RCC. Ongoing research to identify novel agents continues to build upon the work done during the elucidation of the von Hippel-Lindau/clear cell RCC pathway. It is hoped that ongoing and planned studies will enable development of therapeutic regimens that will incorporate agents with improved toxicity and better efficacy as well as defining a role for a multidisciplinary approach to the management of advanced RCC.

Figure 1. Clear Cell Renal Cell Carcinoma Pathways and Targeted Therapies

The VHL gene is mutated in the majority of sporadic clear cell kidney cancer. As a result of mutation, the VHL protein cannot target and degrade hypoxia-inducible factor (HIF) 1 α /2α. HIF overaccumulates and causes increased transcription of downstream genes, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) and transforming growth factor alpha (TGF-α). Current therapeutic approaches include antibodies, such as bevacizumab, that targets VEGF, tyrosine kinase inhibitors such as sunitinib, sorafenib, and pazopanib that target the VEGF and PDGF receptors and rapalogues such as temsirolimus and everolimus that target the mammalian target of rapamycin complex 1 (mTORC1). Future approaches could include agents that target HIF directly including histone deacetylase inhibitors (HDACi) and indirectly via inhibition of the mammalian target of rapamycin complex 2 (mTORC2).