Therapeutic options targeting angiogenesis in nonsmall cell lung cancer

Abstract

There is a major unmet medical need for effective and well-tolerated treatment options for patients with advanced nonsmall cell lung cancer (NSCLC), in both first-line and relapsed/refractory settings. Experimental evidence has validated signalling pathways that regulate tumour angiogenesis, including the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways, as valid anti-cancer drug targets. However, to date, bevacizumab (an anti-VEGF monoclonal antibody) is the only antiangiogenic agent to be approved for the treatment of NSCLC. Many other agents, including antibodies, small-molecule tyrosine kinase inhibitors and vascular disrupting agents, have been assessed in phase III trials but have generally failed to demonstrate clinically meaningful benefits. This lack of success probably reflects the redundancy of proangiogenic pathways and the molecular and clinical heterogeneity of NSCLC. In this review we summarise recently completed and ongoing randomised clinical trials of emerging antiangiogenic agents in patients with NSCLC. We highlight recent promising data with agents that simultaneously inhibit multiple proangiogenic pathways, including the PDGF and FGF pathways, as well as the VEGF pathway. Finally, we discuss the outlook for antiangiogenic agents in NSCLC, emphasising the need for clinically validated prognostic and predictive biomarkers to identify patients most likely to respond to therapy.

Figure 1.

Molecular pathways underlying angiogenesis. A: Tumour cells produce vascular endothelial growth factor (VEGF)-A and other angiogenic factors, such as basic fibroblast growth factor (bFGF), angiopoietins, interleukin-8, placental growth factor and VEGF-C. These stimulate resident endothelial cells to proliferate and migrate. B: An additional source of angiogenic factors is the stroma. This is a heterogeneous compartment, comprising fibroblastic, inflammatory and immune cells. Recent studies indicate that tumour-associated fibroblasts produce chemokines, such as stromal cell-derived factor (SDF)-1, which may recruit bone-marrow-derived angiogenic cells (BMC). VEGF-A or placental growth factor may also recruit BMC. Tumour cells may also release stromal cell-recruitment factors, such as platelet-derived growth factor (PDGF)-A, PDGF-C or transforming growth factor (TGF)-β. A well-established function of tumour-associated fibroblasts is the production of growth/survival factor for tumour cells, such as epidermal growth factor (EGF) receptor ligands, hepatocyte growth factor and heregulin. C: Endothelial cells produce PDGF-B, which promotes recruitment of pericytes in the microvasculature after activation of PDGF receptor-β. HGF: hepatocyte growth factor. Reproduced from [10] with permission.