The Contribution of DNA Methyltransferase Inhibitors in Treating Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a broad, complex group of cancers characterized by the inability to form mature, healthy blood cells. There are different types with varying degrees of risk associated, making it difficult to diagnose and treat. Additionally, many patients are symptom-free and at an older age where they are likely to have other life-threatening ailments. Although there is no specific known cause, genetics, as well as DNA damaging agents, seem to contribute to these types of cancer. Managing symptoms and progression of the disease is the goal once diagnosed with MDS. This is done via an intense risk stratification system; individuals are either low, intermediate or high risk depending on a specific pattern and degree of cytopenias, serum erythropoietin (sEPO) level, presence of a genetic deletion (del(5q)), marrow cellularity, age and comorbid conditions.¹

DNA Methyltransferase Inhibitors for MDS

DNA methylation is an epigenetic reaction that contributes to gene expression; whether a gene is turned on or off. Methylation occurs by the addition of a methyl group to the C5 position of cytosine at CpG dinucleotides catalyzed by the DNA methyltransferase enzyme.² In several cancers including MDS, genes that regulate growth, differentiation, or apoptosis could become inactivated due to DNA hypermethylation.³ According to Saba et al., multiple genes are hypermethylated in MDS including one that increases during disease progression to acute myeloid leukemia (AML).³

Fortunately for MDS patients, two FDA approved drugs (azacitidine or decitabine) are available as DNA methyltransferase inhibitors, therefore, slowing the effects of hypermethylation. When DNA is replicated in the cell, these hypomethylating agents are capable of incorporating and irreversibly binding to stop DNA methyltransferase from doing so, which ultimately leads to reversing epigenetic suppression of genes.⁴ These inhibitors have become extremely useful in treating patients with MDS. In fact, once they stop working due to intolerance, resistance, or relapse after a favorable response, there is no approved second-line therapy, and the outlook is poor with a low survival rate.¹

DNA Methyltransferase Inhibitors for Other Indications

Turns out, cancer isn’t the only disease in which DNA methyltransferase inhibitors can lend a hand. The epigenetic effects of DNA methylation are seen in an array of biological functions.  Researchers have found exciting potential benefits for cardiovascular disease (CVD) and inflammatory disorders.² Specifically, Hydralazine (a DNA methyltransferase inhibitor) has been recently FDA approved as an anti-hypertensive drug.² Although there have been some thrilling findings as of late, more investigation in this area is needed.

High throughput activity assays can be used to find novel drugs for DNA methyltransferase targets. BellBrook’s AptaFluor Methyltransferase Assay directly detects SAH produced by enzymes providing a universal method for inhibitor screening.  Once hits are discovered, the assay can also be used to determine inhibitor potency during SAR campaigns and lead optimization initiatives. New therapeutics could lead to treatments for a variety of diseases including MDS.

Learn About the Methyltransferase Assay

References

1. Steensma DP. Myelodysplastic syndromes current treatment algorithm 2018. Blood Cancer J. 2018. doi:10.1038/s41408-018-0085-4 https://www.nature.com/articles/s41408-018-0085-4
2. Nicorescu I, Dallinga GM, de Winther MPJ, Stroes ESG, Bahjat M. Potential epigenetic therapeutics for atherosclerosis treatment. Atherosclerosis. 2019;281(October 2018):189-197. doi:10.1016/j.atherosclerosis.2018.10.006. https://www.ncbi.nlm.nih.gov/pubmed/30340764
3. Saba HI. Decitabine in the treatment of myelodysplastic syndromes. 2007;3(5):807-817. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376088/
4. Press D. Decitabine in the treatment of acute myeloid leukemia in elderly patients. 2014:53-61. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917925/
5. Tandon B, Lee Y, Wartman LD, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. New England Journal. 2016:2023-2036. doi:10.1056/NEJMoa1605949 https://www.ncbi.nlm.nih.gov/pubmed/27959731