Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy

Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro-and anti-angiogenic factors. Nearly four decades ago, VEGF was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFR). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for approximately 20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently normalize tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. How-ever, the ability of these agents to reprogram the immunosup-pressive tumor microenvironment into an immunostimulatory milieu has rekindled interest and has led to the FDA approval of seven different combinations of VEGF/VEGFR pathway inhibi-tors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/-VEGFR, and potential strategies to develop more effective ther-apeutic approaches.

Automated summary

Angiogenesis is an important mechanism used by solid tumors to recruit blood vessels for growth. Drugs targeting the VEGF/VEGFR pathway have been approved for various solid tumor types, but the survival benefits have been limited. However, these drugs have the potential to reprogram the tumor microenvironment, leading to the approval of combinations with immune checkpoint blockers. Understanding the mechanisms of response and resistance to these drugs is crucial for developing more effective therapeutic approaches.