Abstract 2533: SGI-110 priming sensitizes hepatocellular carcinoma cells to oxaliplatin
Authors: Kuang Yuting , El-Khoueiry Anthony , Taverna Pietro , Ljungman Mats , Neamati Nouri 
Published: August 2015

Abstract
Promoter DNA hypermethylation is associated with hepatocellular carcinoma (HCC), suggesting the potential utility of demethylating agents in this disease. Here we performed preclinical evaluation of SGI-110, a second generation hypomethylating agent (HMA) formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine that yields longer half-life and more extended DAC exposure than DAC IV infusion, in HCC models to guide the design of a phase I/II trial.
HCC cell lines and a xenograft model were used to determine antitumor activity of SGI-110 as a single agent and when combined with oxaliplatin. Bromouridine-labeled RNA sequencing (Bru-seq) was employed to elucidate the effects of SGI-110 and/or oxaliplatin on genome-wide transcription and to identify potential pharmacodynamics markers.
We found that pretreatment with low doses of SGI-110 significantly synergized with oxaliplatin for improved cytotoxicity. In SNU-398 cells, low-dose oxaliplatin single treatment at 1 μM only inhibited colony formation by 15%, while pretreatment with SGI-110 at 50 nM increased the inhibition to 54%, and pretreatment with SGI-110 at 100 nM further increased the inhibition to 94%. The combination of SGI-110 and oxaliplatin was well tolerated in vivo and significantly delayed tumor growth in mice compared to oxaliplatin alone. On day 19, when average tumor sizes in control and oxaliplatin treatment groups passed the experiment end point of 2000 mm3, the average tumor size was 1010 ± 247 mm3 (p = 0.0039) for SGI-110 treatment alone, and only 391 ± 100 mm3 (p = 0.0001) for combination with oxaliplatin. Bru-seq analysis unveiled inhibitory regulations of genes involved in WNT/EGF/IGF signaling, which are signature pathways contributing to HCC, and certain other cancer genes by SGI-110 and the combination treatment. DNMT1, survivin and ephrin-B2 were identified as novel pharmacodynamics markers for the efficacy of the combination treatment.
In conclusion, SGI-110 priming efficiently sensitizes HCC cells to oxaliplatin by inhibiting distinct signaling pathways, allowing for high antitumor activity without systemic toxicity. These results provide a strong rationale for clinical evaluation of SGI-110 as a single agent and in combination with oxaliplatin at low doses in HCC patients, where the newly identified DNMT1, survivin and ephrin B2 could be used as potential pharmacodynamics markers. In addition, inhibition of the WNT/EGF/IGF signaling pathways by the combination of SGI-110 and oxaliplatin provides a distinct strategy for future design of HCC treatment.
Citation Format: Yuting Kuang, Anthony El-Khoueiry, Pietro Taverna, Mats Ljungman, Nouri Neamati. SGI-110 priming sensitizes hepatocellular carcinoma cells to oxaliplatin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2533. doi:10.1158/1538-7445.AM2015-2533