Anti-angiogenic therapy in the treatment of advanced renal cell cancer

Summary

Metastatic renal cell cancer is associated with a poor prognosis and is resistant to traditional chemotherapy agents. The majority of tumours are associated with inactivation of the von Hippel-Lindau gene and subsequent overexpression of proangiogenic factors, including vascular endothelial growth factor (VEGF). Drugs targeting these pathways have undergone clinical testing in renal cell cancer with encouraging results. This type of therapy is set to revolutionise the treatment of renal cell cancer and this review outlines recent evidence from clinical trials investigating the most promising of these agents.

Introduction

Renal cell cancer (RCC) accounted for 3356 deaths in the UK in 2003, 2% of the total number of cancer deaths.¹ It is more common in men than women with the peak incidence in the 50–70 year age group. The most common type of RCC, clear cell cancer, originates from the proximal renal tubular epithelium and is characterised by clear or granular cell appearance under light microscopy. If disease is detected at an early stage curative surgery, most often radical nephrectomy, can be performed. However, approximately 30% of patients present with metastatic disease and up to a further 30% of patients will relapse with metastatic disease despite surgery.² For these patients treatment options are limited. RCC is generally resistant to chemotherapy and 5 year survival rates are less than 2%.³ There has been some benefit from cytokine-based therapy with interleukin-2 (IL-2) and/or interferon-α (INF-α)⁴ with response rates of 10–20%, but overall clinical value is limited. More recently an improved understanding of the genetic and molecular changes seen in renal cell cancer have led to interest in vascular endothelial growth factor (VEGF), its receptors (VEGFR) and related pathways as possible targets for the treatment of RCC.

VEGF, also known as vascular permeability factor (VPF) or VEGF-A, is a dimeric glycoprotein that belongs to the platelet derived growth factor (PDGF) superfamily of growth factors. The VEGF family consists of VEGF-A, -B, -C, -D, -E, and placental growth factor.⁵ The gene encoding for VEGF, located on chromosome 6, is spliced into four different isoforms VEGF₁₂₁, VEGF₁₆₅, VEGF₁₈₉, and VEGF₂₀₆.⁶

VEGF exerts its biological effects by binding to one of the transmembrane VEGF receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR). This results in receptor dimerization, activation and autophosphorylation of the tyrosine kinase domain triggering a cascade of complex downstream signalling pathway.⁷

VEGF is known to be of critical importance in both normal and tumour-associated angiogenesis and plays a role in endothelial cell division, migration and survival. VEGF expression is regulated by numerous factors, including other angiogenic factors and cytokines. Expression is also triggered following inactivation of the von Hippel-Lindau tumour suppressor gene and this identifies VEGF as a possible target in the treatment of renal cell cancer.

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant condition characterised by the increased risk of developing a number of tumours including RCC. The VHL gene has been mapped to chromosome 3p25-26⁸ and VHL gene allele deletion has been demonstrated in 84–98% of sporadic renal cell tumours. Under normal circumstances the VHL gene codes for a 213 amino acid protein, pVHL. pVHL targets hypoxia inducible factor (HIF) for ubiquitination and degradation under normoxic conditions.⁹ Under conditions of hypoxia or in the presence of a defective VHL gene HIF does not undergo proteolysis and is constitutively activated. This in turn leads to the induction of VEGF and other hypoxia induced genes (Fig. 1). VEGF overexpression has been confirmed in renal cell tumours and thus represents a promising therapeutic target.10, 11