Abstract 2552: Addition of repositioned-drug dexamethasone improves anti-leukemia synergy between HDAC inhibitors and nucleoside analogs

Abstract

Abstract Acute myeloid leukemia (AML) is a heterogeneous collection of bone marrow clonal disorders that leads to clonal expansion and ineffective hematopoiesis, remaining incurable in the majority of adult patients. The physiopathology of this disease involves impaired epigenetic regulation and resistance to conventional treatment. Such epigenetic marks can be reversed by nucleoside analogs (NA) DNA methyltransferase inhibitors (DNMTis) such as azacitidine (AZA) and decitabine (standard treatment for pre-AML myelodysplastic syndromes; MDS), and histone deacetylase inhibitors (HDACis). These agents synergistically induce re-expression of silenced genes resulting in cell growth arrest, differentiation and apoptosis. We have shown that interactions between NA and HDACis relied on mechanisms modulating activation of pro-survival NA-mediated NF-kB signaling, based on which we analyzed several original transcriptional expression datasets related to the treatment of AZA or HDACis in AML cell lines, xenografts and MDS/AML patients, and identified dexamethasone (DEX) as a candidate repositioned-drug: 1) DEX could suppress the VEGFA, STAT5, inflammatory cytokines, chemokines and their cognate receptors’ gene sets in primary human bone marrow progenitor cells, which are significantly activated in MDS/AML patients resistant to AZA+HDACi treatment; 2) DEX could inhibit the alternative activated signaling molecules responsible for resistance to AZA; 3) two clusters of aberrantly methylated (hypo and hyper) genes examined were significantly enriched in blasts from MDS patients comparing with healthy people, and DEX was able to “normalize” expression of these genes; 4) DEX could suppress the elevated target genes of P210 BCR-ABL gene fusion in MDS patients; and, importantly 5) DEX has wide inhibitory effects on the NF-kB pathway-targeted cytokines, chemokines, and their modulators on human bone marrow CD34+ cells compared to untreated cells. Repositioned DEX was validated in human leukemia cells exposed to HDACi/NA, a situation where a marked reduction in the synergism exists because of strong NF-kB activation. In the presence of DEX, either the drugs alone or in combination displayed a significant increase in lethality, notably in the case of HDACi/NA. As expected from our analysis, DEX inhibited HDACi/NA-induced NF-kB activation in human leukemia cells; importantly, co-administering HDACi/NA with DEX had a major impact on the outcome of the drug combination. This new concept is critically relevant for therapies involving NA and HDACis since AML cells that are still alive after treatment constitute one of the main sources of chemo-resistance. Thus, addition of DEX to the therapeutic intervention which results in almost 100% cell death, may directly affect this small percentage of cells with increased survival capacity, and thereby reduce/delay the probability of relapse. Citation Format: Hong Zhao, Jaime Mejia, Adriana E. Rosato, Swaminathan P. Iyer, Jenny C. Chang, Roberto R. Rosato. Addition of repositioned-drug dexamethasone improves anti-leukemia synergy between HDAC inhibitors and nucleoside analogs. [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 2552. doi:10.1158/1538-7445.AM2015-2552