Abstract 5832: Sphingolipid metabolism determines the efficacy of nanoliposomal ceramide in acute myeloid leukemia

Abstract

Abstract Therapeutic advances for the treatment of acute myeloid leukemia (AML) have been limited in part due to the heterogeneity and complexity of the disease and a poor understanding of its underlying biology. The leukemia stem cell (LSC) arguably resists current therapy resulting in relapses for most initially treatment sensitive patients. AML with myelodysplastic syndrome related changes (AML-MRC) highlights this challenge, representing a very poor outlook subset. The present study sought to understand the underlying sphingolipid biology in and AML, and to evaluate the efficacy of nanoliposomal ceramide (Lip-C6). Sphingolipids play essential roles in cell survival and proliferation, as well as stress and death. Lip-C6, which delivers a short-chain analog of the pro-apoptotic sphingolipid ceramide, has been in development as an anticancer therapeutic. The efficacy of Lip-C6 therapy was evaluated in both in vitro and in vivo models using primary AML cells and AML cell lines. Evaluation and characterization of the effect of treatment with Lip-C6 was done through lipidomic, short term assays such as apoptosis, autophagy and colony formation assays. Efficacy of Lip-C6 and vinblastine was tested in patient derived xenograft models and mouse - human cell line xenograft MV-411. NOD SCID gamma (NSG) mice were injected with luciferase/YFP labeled cells and monitored by bioluminescence imaging (BLI) for the leukemia progression and efficacy. Sphingolipid metabolism was observed to be elevated in patient samples with De Novo AML but not those with AML-MRC. Apoptosis induced by Lip-C6 in CD34+ve/CD38-ve “LSCs” was robust in AML-MRC, but limited in De Novo AMLs. Similarly, AML colonies forming cells were more sensitive to Lip-C6 in AML- MRC than in De Novo cases. It was hypothesized that elevated sphingolipid metabolism and the upregulation of pro-survival pathways such as autophagy contributed to Lip-C6 resistance in De Novo AML. Vinblastine, when combined with Lip-C6, focused sphingolipid metabolism towards pro-apoptotic metabolites and blocked autophagy. In-vivo combination of Lip-C6 and vinblastine uniquely yielded long term control of leukemia progression without systemic toxicity, translating in to prolonged overall leukemia free survival compared to single agents. Altogether, this study shows fundamental biological differences in sphingolipid metabolism between De Novo AML and AML-MRC. The combination of Vinblastine and Lip-C6 targets the LSC and yields apparent cure of lethal human xenograft AML. Citation Format: Charyguly Annageldiyev, Arati Sharma, Brian M. Barth, Todd E. Fox, Tye Deering, Viola Devine, Nicole R. Keasey, Stephan T. Stern, Megan M. Young, Hong-Gang Wan Wang, Jason Liao, Junjia Zhu, Aaron D. Viny, Ross L. Levine, Thomas P. Loughran, Mark Kester, David F. Claxton. Sphingolipid metabolism determines the efficacy of nanoliposomal ceramide in acute myeloid leukemia [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 5832.