Vascular endothelial growth factor A and Delta-like ligand 4 (VEGF-A and DLL4)

Vascular endothelial growth factor A (VEGF-A) and Delta-like ligand 4 (DLL4) are two critical proteins that cooperatively regulate angiogenesis, the formation of new blood vessels from pre-existing ones. VEGF-A is a potent mitogen that drives endothelial cell proliferation and migration, while DLL4 is a Notch pathway ligand that acts as a negative regulator to prevent excessive, chaotic vessel sprouting [1, 11]. In many solid tumors, both pathways are upregulated to support rapid growth and provide a mechanism for resistance to standard anti-VEGF therapies [12, 21]. Bispecific antibodies targeting both VEGF-A and DLL4 aim to disrupt tumor growth by simultaneously reducing vessel density and inducing 'non-productive' angiogenesis, where vessels are formed but remain non-functional and unable to support the tumor's metabolic needs [13, 20]. This dual-targeting approach is currently being evaluated in clinical trials for various malignancies, including biliary tract cancer and platinum-resistant ovarian cancer, as it has shown the potential to overcome resistance seen with single-agent VEGF inhibitors [2, 6, 14].

Other names

VEGF-AVEGFAVascular endothelial growth factor ADLL4Delta-like ligand 4Delta-like protein 4Notch ligand DLL4

Dual inhibition of the VEGF-A and DLL4/Notch signaling pathways to synergistically inhibit tumor angiogenesis and reduce cancer stem cell frequency. VEGF-A inhibition reduces overall vessel density, while DLL4 inhibition induces 'non-productive' angiogenesis characterized by excessive but non-functional vessel sprouting, effectively starving the tumor of nutrients and oxygen [1, 2, 13].