Predicting the Effects of Anti-angiogenic Agents Targeting Specific VEGF Isoforms

摘要: Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, whose effect on cancer and development well characterized. Alternative splicing VEGF leads to several different isoforms, which are differentially expressed in various tumor types have distinct functions blood vessel formation. Many therapies aim inhibit angiogenesis by targeting preventing intracellular signaling leading vascularization; however, the effects specific isoforms received little attention clinical setting. In this work, we investigate selectively single isoform, as compared with inhibiting all isoforms. We utilize molecular-detailed whole-body compartment model transport kinetics presence breast tumor. The includes two major VEGF121 VEGF165, receptors VEGFR1 VEGFR2, co-receptors Neuropilin-1 Neuropilin-2. predict concentrations free VEGF, number VEGF/VEGFR2 complexes (considered be pro-angiogenic), receptor occupancy profiles following inhibition using isoform-specific anti-VEGF agents. that 54% 84% reduction tumors secrete both or overexpress VEGF121, respectively. Additionally, 21% VEGFR2 molecules ligated 88% when targeted. Targeting reduces an effective treatment strategy. Our results provide basis for investigation