Abstract C233: BAL27862: A unique microtubule-targeted agent with a potential for the treatment of human brain tumors
Authors: Schmitt-Hoffmann Anne , Klauer Dominique , Gebhardt Klaus , Fullhardt Pascal , Brendle Alain , Hardgreaves Patrick , Schlaefle Caroline , Bucher Christian , Spickermann Jochen , Defoin Rosalie , Burger Karin , Vuong Van , Bachmann Felix , Pruschy Martin , Lane Heidi 
Published: June 2012

Abstract
Background: BAL27862 is a synthetic small molecule, potently inducing apoptosis in cancer cells through tubulin depolymerization characterized by a unique microtubule phenotype. BAL27862 has demonstrated a broad in vitro anti-proliferative activity against a range of human tumor histotypes (low nM IC50s). Significant antitumor responses occur in animal models of human cancer after oral or intravenous (i.v.) administration, including tumors refractory to conventional treatments. The purpose of this study was to investigate the tissue distribution of BAL27862 in tumor-bearing mice. Tumor and brain penetration, together with anti-proliferative activity in glioblastoma (GBM) cell lines, is described.
Materials and Methods: Anti-proliferative activity and induction of tumor cell death in vitro were analyzed using the YO-PRO® assay (48h incubation). CD1 nu/nu female mice were implanted with human colon carcinoma SW480 cells. For pharmacokinetic studies, tumor-bearing (approx. 150 mm3) mice were administered i.v. with either 2 mg/kg 14C-BAL27862 (n=6, single dose) or 8 mg/kg cold BAL27862 (n=33, once-weekly during 4 weeks). Animals were culled at serial time points. Radioactivity was measured in slices, with Bio-Imaging Analyzer read-outs of the exposed phosphor imaging plates quantified with Aida software. Cold BAL27862 was determined in plasma, brain and tumors using a specific LC-MS/MS method after sample homogenization and protein precipitation.
Results: BAL27862 elicited a potent anti-proliferative activity in 6 GBM cell lines (IC50 range: 10–20nM), which was independent of PTEN status. Strikingly, at optimal concentrations, a dramatic loss of cell viability was observed (% cell death at 50nM BAL27862: &gt;15% in 5 lines, &gt;30% in 2 lines), demonstrating that BAL27862 potently drives GBM cells into a cell death program..In mice, after i.v. administration of 14C-BAL27862, radioactivity was distributed to all organs: notably brain and tumor. A delayed peak was observed in slowly perfused organs such as skin, tumor and fat-tissue. There was no tissue-specific retention of radioactivity, as halflives were comparable between tissues and blood. 48h after administration, radioactivity was almost undetectable in most tissues. Following administration of 8 mg/kg i.v. cold BAL27862 to mice, the excellent brain and tumor penetration was confirmed. Specifically, similar levels of BAL27862 were found in brain and plasma (Cmax of 6.86 µg/g and 7.34 µg/mL, respectively). The ratio tumor/plasma was also around 1. There was no brain or tumor accumulation over time, as concentrations paralleled those in plasma.
Conclusions: BAL27862 is efficiently distributed to tissues and tumor in a mouse model of human cancer. Significant brain penetration, coupled with cytotoxic activity in GBM tumor cell lines, would support further evaluation of BAL27862 for the treatment of human brain cancers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C233.