Abstract 1013: Treatment of EBV-positive nasopharyngeal carcinoma xenografts with the HDAC-inhibitor Abexinostat: synergy with cis-platinum.
Authors: Vérillaud Benjamin , Gressette Mélanie , Jimenez Anne-Sophie , Lelièvre Hélène , Lo Kwok-Wai , Jacquet-Bescond Anne , Kraus-Berthier Laurence , Depil Stéphane , Busson Pierre 
Published: August 2014

Abstract
Epstein-Barr virus (EBV) related nasopharyngeal carcinoma (NPC) is the third leading cause of virus-related human malignancy. On average, NPCs are more radiosensitive and chemosensitive than other head and neck tumors. However, local relapse and distant organ metastases still raise serious therapeutic problems. The aim of this study was to investigate the potential of the novel pan-HDAC inhibitor Abexinostat (S78454) for the treatment of NPC. Three types of EBV-positive NPC cells have been used as targets for in vitro and in vivo treatments. C666-1 and C17 cells were first xenotransplanted from the patients to nude mice and, in a second stage, adapted to permanent in vitro culture. In contrast, C15 cells are still propagated exclusively as xenografts; however, they can be used in short term culture assays. S78454 was applied to these cells either alone or in combination with cis-platinum. All three types of NPC cells - C666-1, C15 and C17 - were sensitive to the cytotoxic effects of Abexinostat with IC50 of 220, 150 and 200 nM, respectively. Combined treatment of Abexinostat with cis-platinum resulted in a synergistic effect with Bliss additivism index of 34, 33 and 19, respectively. In the next step, we used xenografted NPC cells for in vivo assessment of Abexinostat. Tumor-bearing mice were treated for 3 weeks. The compound was administered by intra-peritoneal injections, twice a day; 4 days a week, at a dose of 12.5 mg/Kg. Cis-platinum (2mg/Kg) was delivered once a week. In these experimental conditions, cis-platinum had no effect on tumor growth when used as a single agent. In contrast, Abexinostat by itself induced a significant decrease in tumor growth. This clinical effect was accompanied by a substantial decrease in the concentrations of Rad 51 and Rad 23B proteins in xenografted NPC cells for all 3 tumor lines. An increase in the concentration of acetylated tubulin was observed for only one type of xenografted NPC (C666-1). A strong synergistic anti-tumor effect was obtained when Abexinostat was combined with cis-platinum. It was manifested clinically by a spectacular inhibition of tumor growth and at histological examination by extensive areas of fibroblast proliferation segmenting and pushing residual tumor areas. These results support implementation of phase I/II clinical trials of Abexinostat for the treatment of NPC, especially in association with cis-platinum. The fact that Abexinostat was active against NPC xenografts at a relatively low dose (25mg/kg/day) suggests that it might have a better therapeutic index in NPC patients than in patients bearing other types of carcinomas. Down-regulation of Rad51 in tumor cells seems to be more consistent that the increase in acetylated tubulin. Additional investigations will be required to determine whether this change is predictive of a long term favourable tumor response to Abexinostat.
Citation Format: Benjamin Vérillaud, Mélanie Gressette, Anne-Sophie Jimenez, Hélène Lelièvre, Kwok-Wai Lo, Anne Jacquet-Bescond, Laurence Kraus-Berthier, Stéphane Depil, Pierre Busson. Treatment of EBV-positive nasopharyngeal carcinoma xenografts with the HDAC-inhibitor Abexinostat: synergy with cis-platinum. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1013. doi:10.1158/1538-7445.AM2013-1013