Angiogenesis Inhibition using VEGF Receptor Blockade Approach

摘要

Angiogenesis is the process of new blood vessel formation from existent vascular network and it is tightly regulated by a balance between pro- and anti-angiogenic factors [1]. Physiologically, angiogenesis is activated in wound healing, ovulation and menstruation. However, it is also observed in pathologic conditions such as cancer, macular degeneration in the eyes and others. Angiogenesis has been highly explored as drug target in cancer therapy after observations that tumors can only grow beyond a few millimeters when well supplied by vascular vessels [2]. Anti-antiogenic therapies have been demonstrated as an alternative to adjuvant therapy in cancer treatment after the correlation between angiogenesis and cancer development [2] was established. Our laboratory has developed peptide-based cancer vaccines with emphasis on the conformational epitopes of HER-2 which is over-expressed in at least 25% of breast cancer [3,4]. Expression of VEGF induced by HER-2 positive tumors led us to target VEGF dependent angiogenesis as a combination therapy. Our long term goal is to develop angiogenic inhibitors that can be used in combination with breast cancer peptide vaccines [3,4]. In this work, we focus on the VEGF activated pathway and propose an approach to interrupt VEGF and VEGFR2 receptor interaction using peptides designed to mimic the VEGF binding site. The interaction between VEGF and VEGFR-2 has been mapped by alanine scanning showing that the binding site is most localized at loop between β5- β6. This loop corresponds to "hot spots" for VEGF binding, which includes monoclonal epitope binding (Avastin, G-6 and B20-4) and VEGF receptors binding sites. We selected the VEGF sequence surrounding residues 70-100 to design a VEGF peptide mimic.