Abstract
Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals.
Highlights
Molecules that bind to different sites within the tubulin polymer can produce varied molecular outcomes and confer anticancer activity in diverse tumor indications
The compound BNC105 exhibited the highest degree of selectivity, being 80 times more active against activated endothelial cells than against quiescent endothelial cells (Table 1A)
To confirm that the selectivity displayed for activated endothelial cells is not restricted to HUVEC, we investigated the activity of BNC105 against activated and quiescent HAAEC HAAE-1 cells
Summary
Molecules that bind to different sites within the tubulin polymer can produce varied molecular outcomes and confer anticancer activity in diverse tumor indications. Several agents have been described that bind at the colchicine site and are capable of causing blood vessel disruption within solid tumors. This class of compounds is defined as vascular disruption agents (VDA). The preclinical evaluation of tubulin-targeting VDAs has shown that these compounds are able to disrupt tumor blood flow, causing tumor hypoxia and necrosis [5]. We used two in vitro correlates of endothelial cell function to screen this library for compounds that exhibit selectivity for endothelial cells that are in a state of activation or angiogenesis This effort led to the discovery of a novel tubulin-targeting agent, BNC105. This increased therapeutic window enables administration of BNC105 at higher dose levels, yielding single-agent efficacy in human xenograft tumor models
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