Abstract
Despite advancements in cancer therapeutics, acute myeloid leukemia patients over 60 years old have a 5-year survival rate of less than 8%. In an attempt to improve this, epigenetic modifying agents have been combined as therapies in clinical studies. In particular combinations with Decitabine and Vorinostat have had varying degrees of efficacy. This study therefore aimed to understand the underlying molecular mechanisms of these agents to identify potential rational epi-sensitized combinations.Combined Decitabine-Vorinostat treatment synergistically decreased cell proliferation, induced apoptosis, enhanced acetylation of histones and further decreased DNMT1 protein with HL-60 cells showing a greater sensitivity to the combined treatment than OCI-AML3. Combination therapy led to reprogramming of unique target genes including AXL, a receptor tyrosine kinase associated with cell survival and a poor prognosis in AML, which was significantly upregulated following treatment. Therefore targeting AXL following epi-sensitization with Decitabine and Vorinostat may be a suitable triple combination. To test this, cells were treated with a novel triple combination therapy including BGB324, an AXL specific inhibitor. Triple combination increased the sensitivity of OCI-AML3 cells to Decitabine and Vorinostat as shown through viability assays and significantly extended the survival of mice transplanted with pretreated OCI-AML3 cells, while bioluminescence imaging showed the decrease in disease burden following triple combination treatment.Further investigation is required to optimize this triple combination, however, these results suggest that AXL is a potential marker of response to Decitabine-Vorinostat combination treatment and offers a new avenue of epigenetic combination therapies for acute myeloid leukemia.
Highlights
Acute myeloid leukemia (AML) is the most common form of adult leukemia with disease heterogeneity contributing significantly to variability in patient outcomes
Further investigation is required to optimize this triple combination, these results suggest that AXL is a potential marker of response to DecitabineVorinostat combination treatment and offers a new avenue of epigenetic combination therapies for acute myeloid leukemia
To evaluate potential synergy between these epigenetic modifying therapies (EMTs), cell lines were treated with a range of dose combinations and the combination index (CI) was calculated using Calcusyn software as described in the methods
Summary
Acute myeloid leukemia (AML) is the most common form of adult leukemia with disease heterogeneity contributing significantly to variability in patient outcomes. Survival rates of younger patients have increased in recent years, there has been little improvement for elderly patients Old) who still have a 5 year survival rate of less than 8% [1]. Subclassification of AML has greatly improved during this time, little progression has been made in developing effective targeted therapies for the treatment of AML. Aberrant epigenetic modifications including methylation (DNA and histone) and acetylation (histone) are key contributors to leukemia initiation and maintenance [3]. A number of epigenetic modifying therapies (EMTs) have shown promise in reversing these abnormal patterns and reinstating an epigenetic landscape that resembles a more normal state. As early as 1999, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) were shown to have synergistic antitumor activities through the re-expression of silenced genes [4]
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