Abstract 387: Activating transcription factor 3 (ATF-3) expression is a potential marker of tumor response to the HDAC inhibitor Pracinostat

Abstract

Abstract BACKGROUND: Bladder cancer is the fifth most common cancer affecting the Western world. About 90% of bladder cancer is superficial and the remaining 10% is muscle invasive. Surgery followed by platinum based chemotherapy is the standard treatment for high grade tumors, and results in <50% 5 year survival rate following surgery. ATF3 can play a key role as either an oncogenic suppressor or an inducer depending on the degree of malignancy. Decreased ATF3 expression in bladder cancer has been associated with tumor progression and a reduced survival rate [1]. Pracinostat (SB939) is an orally available highly potent histone deacetylase inhibitor with a sustained inhibitory effect on tumor tissues [2]. This study aimed to determine whether ATF3 expression which is silenced in bladder cancer could be induced by Pracinostat and used as a potential marker of response in HDACi mediated cancer therapy. METHODS: A series of human bladder cancer cell lines of different grades and origin were utilized to characterize ATF3 expression. Proliferation, clonogenecity and migratory properties of Pracinostat treated cells were assayed by vialight, soft agar and scratch wound methods respectively. Athymic balb/c mice were used to study in vivo anti tumor effect. RESULTS: Treatment with Pracinostat activated the expression of ATF3 in a time and dose depended manner coincident with acetylation of histone 3 and 4. Pracinostat treated cells exhibited a dose depended effect on migratory properties that was abrogated in cells where ATF3 was depleted using short hairpin siRNA knockdown. Treatment with Pracinostat also showed a significant effect on proliferative and colony forming capacity of bladder cancer lines and induced growth arrest at the G1/G0 phase of the cell cycle and retinoblastoma (Rb) activation. In vivo experiments demonstrated a significant reduction in the tumor volume of the Pracinostat treated mice compared to the control group. Furthermore, reactivation of ATF3 expression was detectable in xenograft tumor cells which were in non - proliferating state. CONCLUSION: HDAC inhibitor Pracinostat activated expression of ATF3 has a significant impact on the malignant behavior of bladder cancer cell lines in vitro including activation of tumor suppressor genes and cell growth arrest. Pracinostat shows efficacy as an anti tumor agent in bladder cancer xenografts accompanied by reactivation of the expression of ATF3 suggesting its potential as a biomarker of response. 1.Yuan, X., et al., ATF3 Suppresses Metastasis of Bladder Cancer by Regulating Gelsolin-Mediated Remodeling of the Actin Cytoskeleton. Cancer Research, 2013. 73(12): p. 3625-3637. 2.Novotny-Diermayr,V.,et al.,SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer. Molecular Cancer Therapeutics, 2010. 9(3): p. 642-652. Citation Format: Dhanya Sooraj, Dakang Xu, Jason Cain, Daniel Gold, Bryan R. Williams. Activating transcription factor 3 (ATF-3) expression is a potential marker of tumor response to the HDAC inhibitor Pracinostat. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 387. doi:10.1158/1538-7445.AM2014-387