Abstract 580: Chemical transcriptomic analysis illuminates a class of anticancer sulfonamide derivatives undergoing clinical investigation

Abstract

Abstract Microarray-based gene expression analysis allows us to understand a comprehensive transcriptional profile as one of the fine cellular phenotypes after anticancer drug treatment. Analytical programs with bioinformatics are also useful to connect a gene expression fingerprint pattern with relevant cellular pathways to drug treatment. We have so far tested more than 40 anticancer small molecules, including standard drugs and investigational ones, with respect to their transcriptional profiles using a unified microarray assay condition. Interestingly, our pilot study to evaluate14 different anticancer agents simultaneously using Affymetrix GeneChip arrays illuminated that 6 sulfonamide derivatives had highly correlated transcriptional profiles with cosine coefficients being more than 0.70 in all pairwise combinations. By contrast, cosine coefficients were less than 0.30 in all combinations between one from the 6 sulfonamide derivatives and the other from the remaining 8 test compounds. These sulfonamide derivatives consist of chloroquinoxaline sulfonamide (CQS), LY186641 (sulofenur), LY295501, LY573636 (tasisulam), E7070 (indisulam) and E7820, all of which have been actively investigated in clinical trials. Among them, LY573636 is a most advanced agent, currently undergoing a phase III study in comparison with paclitaxel as second line treatment in patients with melanoma. E7820 is also being evaluated in a phase II study in combination with cetuximab in patients with refractory metastatic colorectal cancer. To examine whether these 6 sulfonamide derivatives truly share the same cellular target and mechanism of action (MOA), we further carried out 40 cancer cell line COMPARE analysis and cell-based cross-resistance assays. In the former experiment, these 6 sulfonamide derivatives demonstrated very similar antiproliferative meangraph profiles with Pearson's correlation coefficients being more than 0.82 in all pairwise combinations. The latter experiment revealed that two E7070-resistant sub-clonal colorectal cancer cell lines HCT116-C9C1 and -C9C4 were cross-resistant to the other 5 sulfonamide derivatives than E7070. Importantly, the drug resistance mechanism was considered irrelevant to P-gp overexpression. Despite long and intensive exploratory researches, the precise cellular target and MOA of this class of anticancer agents have yet to be fully elucidated. A piece of information has been reported on the production of reactive oxygen species and mitochondria-mediated cellular apoptosis with LY573636 and E7820, independently. Our chemical transcriptomic profiling and pathway analysis herein define a novel class of anticancer sulfonamide derivatives. The present data may provide some insight into their unique MOA based on the distinctive and profound down-regulation of sets of critical cellular metabolism genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 580. doi:10.1158/1538-7445.AM2011-580