Antiangiogenic Agents and Vascular Disrupting Agents for the Treatment of Lung Cancer: A Review

Abstract

Although lung cancer therapy has slowly improved with standard cytotoxic chemotherapy drugs, we have reached an efficacy plateau. The addition of targeted agents, such as those with antiangiogenesis activity, to chemotherapy can improve response and survival outcomes. The first of these agents to gain approval in lung cancer in October 2006 was the antivascular endothelial growth factor antibody, bevacizumab. Small molecule tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor also have proven activity and are under active investigation. Vascular disrupting agents target existing tumor vasculature leading to tumor necrosis, and are being studied in solid tumors, including lung cancer, both as single agents and in combination with chemotherapy. This article will review these new targeted antiangiogenic and antivascular agents with a focus on their use as lung cancer therapeutics.

Cell death-based treatment of lung adenocarcinoma

“…For safety reasons, these agents have been restricted to patients with lung ADC with a low risk of hemoptysis 104 . Patients with squamous cell morphology tumors were excluded from the trial because of an increased risk of bleeding events seen after bevacizumab treatment 105 . The FDA and EMA have approved a novel monoclonal antibody ramucirumab directed to the VEGF receptor for use in combination with docetaxel in the second-line treatment of squamous and non-squamous NSCLCs, although modest but statistically significant improvements in overall and median progression-free survival have been observed regardless of histological subtype 105 .…”

Mechanisms of and strategies for overcoming resistance to anti-vascular endothelial growth factor therapy in non-small cell lung cancer

“…Two phase I studies are currently investigating the combination of TH-302 with an antiangiogenic agent (pazopanib and sunitinib) in patients with solid tumors and have shown promising preliminary activity in 313several treatment-refractory cancers[61,62]. TH-302 is also being studied in an ongoing phase I/II study in combination with bevacizumab in As redundant angiogenic factors are likely among the key mechanisms underlying resistance to anti-VEGF therapy, multitargeted TKIs could be a reasonable solution because they are able to simultaneously inhibit multiple signaling pathways, including those mediated by VEGFRs, PDGFRs, FGF receptors (FGFRs), and c-kit[64]. Results are available for randomized, placebo-controlled trials that have evaluated the therapeutic potential of various multitargeted TKIs in combination with first-line chemotherapy for advanced NSCLC[65][66][67][68] or with the therapy plus chemotherapy versus chemotherapy alone.…”

Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor

“…While several antiangiogenic agents have been developed that inhibit a single pathway, agents that inhibit multiple signaling pathways, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and others, are also under investigation ( Fig. 1) [1,7,8]. Several PDGF receptor tyrosine kinases (PDGFR TKs), are expressed on endothelial cells and pericytes and control important cellular mechanisms such as stability of blood vessel walls, endothelial cell survival, and pericyte-endothelial cell contact [9][10][11].…”