Abstract 679: SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome .
Authors: Tellez Carmen S. , Grimes Marcie J. , Picchi Maria A. , Liu Yushi , March Tom H. , Oganesian Aram , Taverna Pietro , Belinsky Steven A. 
Published: August 2014

The DNA methyltransferase inhibitors (DNMTi) Vidaza (5-azacytidine) and Dacogen (5-aza-2′-deoxycytidine, decitabine) are approved by the FDA for chemotherapy against myelodysplastic syndrome, a heterogeneous bone marrow disorder. Vidaza in combination with the HDAC inhibitor entinostat has shown some promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of these DNMTi against solid tumors is likely impacted in part, by their stability and rapid inactivation by cytidine deaminase in the liver. These studies were initiated to test the efficacy of SGI-110, a prodrug for decitabine. SGI-110, a dinucleotide consisting of 5-aza-2′-deoxycytidine followed by a deoxyguanosine, has been shown to be effective in vitro as a DNA methylation inhibitor and less prone to deamination by cytidine deaminase. In this study, we used our in vivo lung cancer model to explore the potential therapeutic effect of SGI-110 alone and in combination with entinostat. In vivo plasma concentrations and pharmacokinetic properties of SGI-110 and its metabolite decitabine were evaluated in nude rats after a single SC dose of SGI-110. Upon SC administration, SGI-110 is rapidly converted to decitabine. Dose proportional pharmacokinetics showed no significant difference in accumulation of SGI-110 or decitabine, while the half life of decitabine was increased to 4hrs. SGI-110 alone or in combination with entinostat significantly reduced tumor burden by 56% of Calu-6, a K-ras/p53 mutant lung adenocarcinoma cell line engrafted orthotopically in nude rats. On a molecular level, global changes in gene profiles were associated with a reduction in tumor burden. Microarray analysis revealed that a 212 and 592 genes were differentially expressed in SGI-110 alone or with combination therapy. Highly significant gene expression changes were seen in key cancer regulatory pathways. In addition, SGI-110 treatment activated p21 and apoptotic genes BIK and BAK in these tumors. SGI-110 caused widespread epigenetic reprogramming that induced demethylation of an average of 291 genes; in particular 208 genes were polycomb target genes. The polycomb targets were enriched for transcription factors. These preclinical in vivo findings demonstrate that SGI-110 alone shows strong demethylating activity and when combined with entinostat more effectively retards tumor growth. (Supported by Astex Pharmaceutical and SU2C)

Citation Format: Carmen S. Tellez, Marcie J. Grimes, Maria A. Picchi, Yushi Liu, Tom H. March, Aram Oganesian, Pietro Taverna, Steven A. Belinsky. SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome . [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 679. doi:10.1158/1538-7445.AM2013-679