Targeting anionic phospholipids on tumor blood vessels and tumor cells

Abstract

Vascular targeting agents (VTAs) bind selectively to molecules that are present on tumor vasculature, and either recruit host effector cells or deliver agents that occlude or destroy tumor blood vessels [1]. This leads to an avalanche of tumor cell death through deprivation of oxygen and nutrients. VTAs have a number of advantages over other cancer therapies. First, a single vessel provides the nutrition and waste removal for hundreds or thousands of tumor cells, and only has to be damaged at a single point to block blood flow upstream and downstream. Second, the endothelial cell is in contact with the blood stream ensuring rapid drug delivery. Third, the target is unlikely to acquire genetic mutations that render it drug resistant. Fourth, VTAs act on existing as well as newly forming tumor vasculature. Finally, VTAs preferentially kill the hypoxic core regions of tumors, where the vasculature is most stressed and compromised, thus providing a complementary pattern of killing to chemotherapeutic drugs and irradiation, which are most effective against well-oxygenated peripheral regions of tumors. The VTA described in the present article is a naked antibody, bavituximab, which employs host cells as the effectors. Other VTAs employ coupled toxins, procoagulants and pro-apoptotic drugs as effectors. The functionally-similar tumor vascular disrupting agents, such as combretastatin, also occlude tumor vasculature, but do so by exploiting pathophysiological differences between tumor vessels and normal ones, rather than by selectively binding to tumor vessels. The vascular disrupting agents also show improved efficacy when used together with irradiation [2]. Bavituximab stands apart from other VTA and vascular disrupting drugs in causing no significant toxicity by itself and no enhancement of toxicity when combined with other anti-cancer strategies [1].