About Vascular Disrupting Agents
Vascular disrupting agents (VDAs) are a component of VTTs. They exert their antitumor effect by targeting tumor blood vessels, shutting off the blood supply to the interior of the tumor, which deprives tumors of oxygen and essential nutrients, leading to tumor cell death. This is in contrast to the action of currently available AAs, which prevents vascular endothelial growth factor (VEGF)-driven new tumor blood vessel formation, mostly occurring at the rim of tumors.
VDAs rapidly and selectively bind to the colchicine-binding site of β-tubulin, which destabilizes the microtubules and leads to 3-dimensional shape changes of the immature tumor vessel endothelial cells that are not yet anchored by smooth muscle and pericytes. The rounded-up endothelial cells disrupt the tumor blood vessel, thereby leading to widespread ischemia and necrosis of the cancer cells within the central core of the tumor.
An interesting observation of the activity of VDAs is that, in contrast to most conventional cancer therapies, treatment efficacy appears to increase as tumors become larger. We believe this to be a result of larger tumors having a higher interior volume to surface ratio, resulting in a smaller percentage of tumor cells dependent on the normal tissue blood vessels at the rim of the tumor. The increased activity in larger tumors has been characterized in several preclinical studies and initial clinical data appear to support this finding.
In non–tumor-associated blood vessels, this destabilization of tubulin has relatively little effect because these vessels are more mature and have a full complement of endothelial smooth muscle and pericyte coverage that helps maintain their shape when exposed to VDAs.
We believe that utilizing VDAs and AAs in combination will destroy blood vessels in the interior of the tumor while preventing the formation of new tumor blood vessels. Preclinical and initial clinical data support the therapeutic potential of utilizing VDAs combined with AAs in a range of tumor types.