Abstract 2940: Chemosensitization of cholangiocarcinoma by guadecitabine

Abstract

Abstract Cholangiocarcinoma (CC) originates from biliary epithelial cells and is one of the most common hepatobiliary cancers second only to hepatocellular carcinoma. CC patients have poor long-term prognosis and have limited treatment options. Currently, a combination of gemcitabine and cisplatin is used for systemic treatment of CC patients. There are several tumor suppressor genes that are epigenetically inactivated in CC including p16INK4a, RASSF1A and SEMA3B. Guadecitabine is a next-generation hypomethylating agent that has never been tested in biliary cancer cells. It is a dinucleotide of decitabine and deoxyguanosine that is resistant to degradation by cytidine deaminase. Subcutaneous guadecitabine results in a longer window of exposure than IV decitabine in the clinic. The purpose of this study is to examine the effect of this agent alone and in combination with gemcitabine or cisplatin. We found that guadecitabine inhibits cell proliferation of CC cell lines, SK-ChA-1 and Mz-ChA-1, in a dose-dependent manner starting at 125 nM with concomitant inhibition of DNMT1 protein expression. Additionally, there is a dose-dependent induction of PARP cleavage and increase in expression of semaphorin 3B which is highly methylated in CC starting at doses of 125 nM. Sequential treatment with 250 nM guadecitabine for 48 hours and 20 nM gemcitabine or 1 µM cisplatin for 24 hours further inhibits cell proliferation of CC cells compared to either single agent treatments. Furthermore, western blot analysis of sequentially treated cell shows that DNMT1 is inhibited more by combining guadecitabine and gemcitabine than with either single agents or by combining guadecitabine with cisplatin. We also noted induction of PARP cleavage and increase in semaphorin 3B expression in the SGI-110 and gemcitabine combination treatment than in any other condition tested. In a xenograft model of SK-ChA-1 cells, sequential treatment with 2 mg/kg guadecitabine s.c. daily for 1 week and 15 mg/kg gemcitabine i.p. twice a week for 2 weeks significantly reduced tumor growth as compared to single agent therapy. In contrast to the other conditions, this effect continued for up to 18 days after the last treatment. In fact, the sequential treatment reduced tumor growth by 78% and 72% compared to single agent treatments of SGI-110 and gemcitabine, respectively. Furthermore the sequential combination also increased mRNA expression of p16INK4a, RASSF1A and SEMA3B compared to other treatments. However, guadecitabine did not sensitize SK-ChA-1 tumors when combined with 2 weeks of daily 2 mg/kg cisplatin s.c. treatments. In conclusion, guadecitabine is a potent demethylating agent for CC cells that can inhibit tumor growth by itself as well as sensitize the tumor to chemotherapy such as gemcitabine through epigenetic priming. This novel combination is a promising therapy for CC and may represent a significant improvement to current treatment strategies. Citation Format: Oliver Surriga, Gary K. Schwartz. Chemosensitization of cholangiocarcinoma by guadecitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2940.