BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

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. Mol Cancer Ther; 9(6); 1562-73. ©2010 AACR.

Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

“…8 Efficacy in response to BNC105P (the clinically used prodrug of BNC105) has been shown in breast and lung cancer xenograft models. 8,9 The firstin-human clinical trial of BNC105P in solid tumors revealed on-target action of the drug with tubulin disruption seen in a surrogate tissue, peripheral blood mononuclear cells (PBMCs). In this study, 4 of 21 patients with advanced and/or metastatic solid tumors achieved stable disease with the single agent.…”

“…9 However, it has not been tested for efficacy in liquid malignancies. Here, we have determined that BNC105 potently and acutely induces cell death in CLL cells through JNK activation and induction of Noxa at concentrations much lower than either vinblastine or CA4.…”

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

“…1,2 VDAs cause the relatively fast growing and chaotic tumor vasculature to collapse, ceasing tumor blood perfusion with subsequent tumor ischemia, hypoxia and necrosis. VDAs achieve immediate vascular damage and are suited to acute administration regimens, 3 distinct from anti-angiogenic agents such as bevacizumab which require longer term administration.…”

“…3,4 It is thought that the viable cells within the tumor rim activate a suite of adaptive and survival mechanisms implicit to many tumors and are responsible for driving the recovery of the tumor from the VDA treatment. 5,6,7 Given the propensity of tumors to recover from the effects of VDA action, clinical development has sought to investigate agents to use in combination with VDA treatment regimens.…”

Effect of CPU-XT-008, a combretastatin A-4 analogue, on the proliferation, apoptosis and expression of vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells

“…The latter compound has been reported to currently be in phase III evaluation (clinical trial no. NCT00699517) for the treatment of advanced-stage soft tissue sarcoma, following the failure of anthracycline and ifosfamide chemotherapies (17).…”