Therapeutic Approaches Targeting Hypoxic Tumor Vasculature

Tumorigenesis involves the development of a vascular network to support tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis, which can lead to abnormal, dysfunctional morphology. Tumor-associated blood and lymphatic vasculature play a crucial role in supporting immunoevasion and subverting T-cell-mediated immunosurveillance, which are the main hallmarks of cancers. Recent research has shown that blood endothelial cells forming tumor vessels can actively suppress the recruitment, adhesion, and activity of T cells. Additionally, during tumorigenesis, the lymphatic vasculature undergoes dramatic remodeling that facilitates metastatic spreading of cancer cells and immunosuppression. Different alteration has implications such as poor perfusion, tissue hypoxia, and reduced therapy uptake. Targeting tumor angiogenesis as a therapeutic approach has been pursued in various cancers, but traditional antiangiogenic therapeutics have not shown clinical success. Vascular targeting agents (VTAs) are designed to cause a rapid and selective shutdown of tumor blood vessels, leading to tumor cell death and extensive hemorrhagic necrosis. VTAs can indirectly kill tumor cells that are resistant to conventional antiproliferative cancer therapies, such as those in areas distant from blood vessels, where drug penetration is poor. VTAs are expected to show the greatest therapeutic benefit as part of combined modality regimens. There are two types of VTAs: small molecules and ligand-based. Small molecules cause acute vascular shutdown in tumors, leading to massive necrosis, while ligand-based VTAs use antibodies, peptides, or growth factors to target tumors with agents that occlude blood vessels. This book chapter discusses the therapeutic approaches targeting hypoxic tumor vasculature, exploring novel therapeutic approaches for overcoming resistance.