Targeting angiogenesis in metastatic renal cell carcinoma

ABSTRACT

Introduction: Renal cell carcinoma (RCC), and particularly its clear cell histological subtype, is commonly characterized by genetic alterations in the Von Hippel Lindau (VHL) tumor suppressor gene, leading to a typically exasperated angiogenesis. However, other biological and genetic peculiarities contribute to differentiate this malignancy from other solid tumors, including its immunogenicity.

Areas covered: This review focuses on the present and future role of antiangiogenic drugs, administered either alone (as it has been in the past few years), or in combination with other agents (e.g. immune checkpoint inhibitors), in the treatment of metastatic RCC.

Expert commentary: Due to its peculiar pathogenesis, it is unrealistic to expect to be able to get rid of antiangiogenic agents for the treatment of this disease; however, we do expect that combinations of VEGF/VEGFRs-targeting agents with immune checkpoint inhibitors will gradually replace antiangiogenic monotherapies as the standard of care, at least in the first line setting of metastatic RCC patients. Biomarkers discovery remains the highest priority in order to further improve the percentage of patients benefitting of our treatment.

KEYWORDS:

• Tumor angiogenesis
• tyrosine kinase inhibitors
• Von Hippel Lindau gene
• hypoxia-inducible factors
• immunotherapy
• renal cell carcinoma

Article highlights

• Angiogenesis is and still remain a key molecular feature of RCC.

• To date, seven multikinase agents, mainly but not exclusively targeting angiogenesis, have been developed and contributed to dramatically improve, for the better, the prognosis of RCC patients with metastatic disease.

• More recently, some of these agents – in particular, those with higher selectivity and potency against their targets (i.e. VEGFRs) – have been combined with novel immune checkpoint inhibitors, leading to a further improvement in the outcomes of these patients.

• Novel agents and combinations are presently under development, although we still do lack accurate, reproducible and simple/cheap biomarkers to help us to develop a real precision Medicine approach to this malignancy.

Declaration of interest

C. Porta reports acting as a consultant/speaker for Bristol Myers Squibb, Pfizer, Novartis, Ipsen, Eisai, EUSA, Janssen, and General Electrics. A. Mosca reports acting as a consultant/speaker for Bristol Myers Squibb, Pfizer, Novartis, Ipsen, Janssen, and Astellas. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.