Abstract B11: Drug repositioning improves synergistic interactions between HDAC inhibitors and nucleoside analogs in AML and MDS models.
Authors: Zhao Hong , Zhu Rui , Mejia Jaime , Rosato Adriana E. , Iyer Swaminathan , Rosato Roberto R. 
Published: August 2015

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are a heterogeneous collection of clonal disorders of bone marrow disorders that lead to clonal expansion and ineffective hematopoiesis. Patients with higher-risk MDS subtypes often experience rapid disease progression towards AML, facing a life expectancy of less than 1 year. AML remains incurable in the majority of adult patients. The physiopathology of these diseases involves impaired epigenetic regulation in the progression of MDS to AML 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, currently the standard treatment for MDS, and histone tails modifiers histone deacetylase inhibitors (HDACis). These agents synergistically induce re-expression of silenced genes resulting in cell growth arrest, differentiation and apoptosis. Furthermore, we have demonstrated that synergistic effects of combining nucleosides analogs (e.g. fludarabine, AZA, cytarabine) with HDACIs both in vitro and in vivo relied also on mechanisms modulating activation of pro-survival NA-mediated NF-κB signaling. Based on this mechanism centered on NF-κB signaling, we analyzed several original transcriptional expression datasets related to the treatment of AZA or HDACis in AML cell lines, xenografts and MDS/AML patients. A list of possible repositioned drugs was predicted. Upon a detailed comparison among the drugs, Dexamethasone (DEX), an inexpensive medication sporadically used during MDS and AML therapy to treat fever, nausea and allergic reactions, stood out as supported by the following emanating results: 1) DEX could suppress the VEGFA gene set, STAT5 gene set and inflammatory cytokines, chemokines and their cognate receptors gene set in primary human bone marrow progenitor cells, which is significantly activated in MDS/AML patients resistant to AZA+HDACi treatment; 2) DEX could inhibit the alternative activated signaling molecules responsible for the resistance to AZA; 3) two clusters of aberrantly methylated (hypo and hyper) genes were examined significantly enriched in blasts from MDS patients comparing with healthy people, and DEX is able to “normalize” these genes' expression; 4) DEX could suppress the elevated target genes of P210 BCR-ABL gene fusion in MDS patients; and, importantly 5) DEX has a wide inhibitory effects on the NF-κB pathway-targeted cytokines, chemokines, and their modulators on human bone marrow CD34+ cells compared to untreated cells. To validate the repositioning performance of DEX, preliminary assays were performed where human leukemia cells were exposed to HDACi/NA, a situation where exists a marked reduction in the synergism 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. Importantly, co-administering HDACi/NA with DEX had a major impact on the outcome of the drug combination, notably since AML cells that remain alive after HDACi/NA treatment may constitute one of the main sources of chemo-resistance. This new concept is critically relevant for therapies involving NA and HDACIs. In this context, by adding DEX to the therapeutic intervention which results in almost 100% cell death, we may be directly affecting this small percentage of cells that display increased survival capacity, thereby reducing/delaying the probability of relapse.

Citation Format: Hong Zhao, Rui Zhu, Jaime Mejia, Adriana E. Rosato, Swaminathan Iyer, Roberto R. Rosato. Drug repositioning improves synergistic interactions between HDAC inhibitors and nucleoside analogs in AML and MDS models. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B11.