Abstract
Simple SummarySeveral anti-angiogenic drugs have been approved for cancer treatment, alone or in combination with other anti-tumoral agents. Angiogenesis inhibitors cause drug resistance, metastasis formation, and reduced delivery of chemotherapeutic agents, as a consequence of decrease of tumor vasculature. The endothelial cells as gatekeepers inspired a revisited interpretation of the vascular function in several malignancies.Resistance to anti-vascular endothelial growth factor (VEGF) molecules causes lack of response and disease recurrence. Acquired resistance develops as a result of genetic/epigenetic changes conferring to the cancer cells a drug resistant phenotype. In addition to tumor cells, tumor endothelial cells also undergo epigenetic modifications involved in resistance to anti-angiogenic therapies. The association of multiple anti-angiogenic molecules or a combination of anti-angiogenic drugs with other treatment regimens have been indicated as alternative therapeutic strategies to overcome resistance to anti-angiogenic therapies. Alternative mechanisms of tumor vasculature, including intussusceptive microvascular growth (IMG), vasculogenic mimicry, and vascular co-option, are involved in resistance to anti-angiogenic therapies. The crosstalk between angiogenesis and immune cells explains the efficacy of combining anti-angiogenic drugs with immune check-point inhibitors. Collectively, in order to increase clinical benefits and overcome resistance to anti-angiogenesis therapies, pan-omics profiling is key.
Highlights
Several anti-angiogenic drugs have been approved for cancer treatment, alone or in combination with other anti-tumoral agents, and anti-angiogenic therapy is essentially an anti-vascular endothelial growth factor (VEGF) or anti-VEGF-receptor (VEGFR) therapy [1]
Tyrosine kinase inhibitors are additional anti-angiogenic drugs, which interfere with VEGFR-1, VEGFR-2, platelet derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFRs), and Tie2 signaling [3]
VEGF-trap protein aflibercept, obtained by fusion of VEGF binding domain of VEGFR-1 and R-2, which acts as a ‘VEGF ligand trap’, has been approved for the treatment of metastatic colorectal cancer [4]
Summary
Several anti-angiogenic drugs have been approved for cancer treatment, alone or in combination with other anti-tumoral agents, and anti-angiogenic therapy is essentially an anti-vascular endothelial growth factor (VEGF) or anti-VEGF-receptor (VEGFR) therapy [1]. The first anti-angiogenic drug, bevacizumab (Avastin), a humanized anti-VEGF-A monoclonal antibody, was approved for the treatment of previously untreated metastatic colorectal cancers in combination with chemotherapy [2]. Anti-angiogenic drugs lead to an increase in patient’s overall survival (OS) in the range of weeks to months and a 3–6-month increase in progression-free survival (PFS), followed by relapse in tumor angiogenesis and growth. When VEGF-targeted therapies are discontinued, tumor vasculature is rapidly re-established [6], whereas continuation of bevacizumab treatment is associated with an increase in OS [7]. The intent of this literature review is to uncover the state-of-the-art understanding of the key mechanisms supporting angiogenesis and facilitating an immune-tolerogenic environment throughout tumor growth and progression
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