Anti-angiogenic agents have been successful in the clinic for blocking the growth of solid tumors. However, these agents used in combination with chemotherapy have improved the survival of patients with cancers by only several months. Therefore, identification of unrecognized angiogenic pathways that selectively support tumor neo-vessel assembly will increase the efficacy of anti-angiogenic or anti-vascular therapy.
The prototypical vascular targeting agent combretastatin A4 phosphate (CA4P) exerts its anti-angiogenic effect by targeting unstable budding tumor neo-vessels. CA4P is currently being studied in clinical trials in oncology.
In a paper appearing online in advance of print publication of the November issue of the Journal of Clinical Investigation, Shahin Rafii and colleagues from Cornell University provide important mechanistic data demonstrating how CA4P has anti-tumor and anti-angiogenic activity.
The authors find that CA4P selectively targets endothelial cells (flat-shaped cells that make up the inside of blood vessels) but not smooth muscle cells (cells which surround most blood vessels), and induces regression of unstable, newly formed vessels by disruption of Vascular Endothelial-cadherin (VE-cadherin) signaling. VE-cadherin is a protein found at the junctions of overlapping regions of endothelial cells and plays a key role in many aspects of vascular function including, endothelial cell survival, cell migration, cell proliferation and assembly into vessel-like structures.
Dissecting the mechanism whereby CA4P exerts its anti-vascular effect will open up new avenues of research to selectively target tumor neo-vessels and increase the therapeutic window of anti-angiogenic agents.