Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy.

ABSTRACT

The use of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) pathway has been a significant addition to cancer therapy. One of the VEGF family members, VEGF-A (commonly referred to as VEGF), has been demonstrated to be important in angiogenesis. Although the mechanism of action of these antibodies is still under study, the anti-VEGF antibody bevacizumab has been approved for treatment of various solid cancers including colorectal, lung, and breast cancers as well as glioblastoma and renal cell carcinoma. Addition of bevacizumab to chemotherapy as adjuvant therapy in colorectal cancer did not improve disease-free survival. Bevacizumab is being tested in other clinical settings such as adjuvant therapy, maintenance therapy, and in combination with both chemotherapy and other targeted agents such as the epidermal growth factor receptor kinase inhibitor erlotinib. In addition to bevacizumab, other antibody-based therapies targeting the VEGF pathway are being tested. Ramucirumab and IMC-18F1 are monoclonal antibodies that target the VEGF receptors VEGFR-2 and VEGFR-1, respectively. Aflibercept (VEGF-Trap), a peptide-antibody fusion targeting VEGF ligand, is being tested in clinical trials. Much research is focused on identifying biomarkers to predict which patients will benefit from anti-VEGF therapy. Recent results suggest that VEGF single nucleotide polymorphisms may be predictive of patient response to bevacizumab. Improved imaging modalities such as dynamic contrast-enhanced MRI (DCE-MRI) can better characterize the efficacy of anti-angiogenic agents. As anti-VEGF treatments such as bevacizumab have been integrated into the treatment of many different types of cancers, the development of bevacizumab-resistant tumors has become more common. Recent studies show that targeting other angiogenesis signaling pathways such as platelet-derived growth factor-C (PDGF-C), Bombina variagata peptide 8 (Bv8, also known as prokineticin-2), and VEGFR-3 may lead to enhanced response in anti-VEGF resistant tumors. In the future, tailored treatments consisting of combinations of chemotherapy, other targeted therapies, and anti-angiogenesis agents will hopefully result in better patient outcomes.