Abstract LB-359: Extended accumulation of acetylated histone in tumor tissues obtained from the phase I study of CG200745

Abstract

Abstract Extended Accumulation of Acetylated Histone in Tumor Tissues Obtained from the Phase I Study of CG200745 Accumulation of acetylated histone is a physiological phenomenon caused by inhibition of HDACs. We have observed such accumulation in cells, mice and humans when CG200745, our cancer therapeutic candidate, was treated. In the phase I clinical trial (NCT01226407), we had a chance to compare such accumulations in both the blood and tumor tissues. Interestingly, the accumulation in the tissues was maintained much longer than that in the blood and its level was significantly high even at 24 hours after dose. Such difference in histone accumulation has been explained by the different PK profile of CG200745 between the blood and the tumor tissues. Although we have not got PK data from the human tumor tissues yet, the difference was already observed in mice PK studies. Specifically, the half-life of CG200745 in plasma of mice was extremely short like other known HDAC inhibitors (approximately 20 mins), but in tumor tissues, that of CG200745 was as long as approximately 7 hours. In the current human studies, CG200745 is showing a much better PK profile in plasma than that of mice studies. Its half-life even in plasma is observed as several hours and clearance is much lower than other HDAC inhibitors. Actually, the AUC/dose of CG200745 is the highest among all the clinical stage HDAC inhibitors. Taking the extended accumulation of acetylated histone in the tumor tissues and better human PK profile into consideration, we believe that CG200745 with excellent HDAC inhibition will be a promising anticancer intervention in the near future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-359. doi:1538-7445.AM2012-LB-359