The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer.

BNC105 is a tubulin targeting compound that selectively disrupts vasculature within solid tumors. The severe tumor hypoxia and necrosis that ensues translates to short term tumor growth inhibition. We sought to identify the molecular and cellular events activated following BNC105 treatment that drives tumor recovery. We investigated tumor adaptation to BNC105-induced hypoxia in animal models of breast and renal cancer. HIF-1α and GLUT-1 were found to be strongly upregulated by BNC105 as was the VEGF signaling axis. Phosphorylation of mTOR, 4E-BP-1 and elF2α were upregulated, consistent with increased protein synthesis and increased expression of VEGF-A. We sought to investigate the potential therapeutic utility of combining BNC105 with agents targeting VEGF and mTOR signaling. Bevacizumab and pazopanib target the VEGF axis and have been approved for first line use in renal cancer. Everolimus targets mTOR and is currently approved in second line therapy of renal and particular breast cancers. We combined these agents with BNC105 to explore the effects on tumor vasculature, tumor growth inhibition and animal survival. Bevacizumab hindered tumor vascular recovery following BNC105 treatment leading to greater tumor growth inhibition in a breast cancer model. Consistent with this, addition of BNC105 to pazopanib treatment resulted in a significant increase in survival in an orthotopic renal cancer model. Combination treatment of BNC105 with everolimus also increased tumor growth inhibition. BNC105 is currently being evaluated in a randomized phase II clinical trial in combination with everolimus in renal cancer.

BNC105: a novel tubulin polymerization inhibitor that selectively disrupts tumor vasculature and displays single-agent antitumor efficacy.

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.