Various epigenetic techniques

Hypomethylating agents

DNA-demethylating drugs are modified forms of cytidine and work by incorporating into replicating DNA and covalently binding to the catalytic sites of DNA methyltransferases (DNMTs). The DNA methyltransferase inhibitors irreversibly inhibit the enzymatic activities of DNMTs and trigger their proteasomal degradation. Azacitidine and decitabine are nucleoside analogs that inhibit DNMTs and are approved for the use in myelodysplastic syndrome (MDS). Meta-analysis of these agents in MDS has shown improved overall survival and improved time to AML transformation or death. In a subgroup analysis, the survival benefit was limited to azacitidine.[5] Azacitidine can be given subcutaneously at 75 mg/m2 for 7 consecutive days every 4 weeks as an outpatient therapy in low–intermediate- and high-risk (transplant ineligible or unfit) MDS.

Histone deacetylase inhibitors

DNA is associated with histone and nonhistone proteins to form chromatin. Condensation (tight coiling) of the DNA suppresses gene expression. Histone deacetylase (HDAC) inhibition facilitates chromatin decondensation and histone acetylation, leading to activated gene expression. This subsequently results in cell cycle arrest and apoptosis, inhibition of angiogenesis, and alteration of immune response.

Romidepsin, vorinostat, and belinostat are approved for patients with cutaneous T-cell lymphoma who have progressive, persistent, or recurrent disease. Vorinostat is an oral drug which is started at 400 mg/day, while the other two are administered intravenously.[6] Panobinostat is approved for multiple myeloma patients who have progressed on two regimens containing bortezomib and an immunomodulatory agent. Patients on HDAC inhibitors are monitored for myelosuppression, hepatotoxicity, and QTc prolongation.

Isocitrate dehydrogenase inhibitors

IDH1 and IDH2 are enzymes which catalyze the conversion of isocitrate to alpha-ketoglutarate and are part of the citric acid cycle. IDH1 or IDH2 mutations are present in about 20% of patients with AML. IDH inhibitors also called “sidenibs” target cancers with these mutations. Enasidenib and ivosidenib are the FDA-approved oral drugs for IDH2- and IDH1-mutated patients, respectively, with relapsed/refractory AML.[7]

Other therapeutic strategies targeting epigenetics in cancer and future directions

Clustered, regularly interspaced, short palindromic repeats-associated protein 9 is an enzyme which inserts break in DNA and is used to edit genes targeting molecules involved in epigenetic modifications. Similarly, newer drugs such as zebularine, a DNMT inhibitor is found to be more stable and less toxic than azacytidine and decitabine. There are ongoing clinical trials which are exploring combination of epigenetic or “immune-sensitizing” therapeutic agents, such as the DNA methyltransferase inhibitors, with immune-checkpoint inhibitors, such as those that block CTLA-4 and programmed death 1 for the treatment of multiple cancers.[8] Thus, cancer epigenetics is an area of ongoing research that has led us to an era of comprehensive medical understanding of complex molecular pathogenesis and identifying novel therapeutic targets.

Conflict of Interest

There are no conflicts of interest.

References

1. Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med 2018; 378: 1323-34
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3. National Institutes of Health. Available from: http://commonfund.nih.gov/epigenomics/figure.aspx. [Last accessed 2020 May 30].
4. Hamamoto R, Komatsu M, Takasawa K, Asada K, Kaneko S. Epigenetics analysis and integrated analysis of multiomics data, including epigenetic data, using artificial intelligence in the era of precision medicine. Biomolecules 2019; 10 DOI: 10.3390/biom10010062.
5. Gurion R, Vidal L, Gafter-Gvili A, Belnik Y, Yeshurun M, Raanani P. et al. 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome—A systematic review and meta-analysis. Haematologica 2010; 95: 303-10
6. Zagni C, Floresta G, Monciino G, Rescifina A. The search for potent, small-molecule HDACIs in cancer treatment: A decade after vorinostat. Med Res Rev 2017; 37: 1373-428
7. Liu X, Gong Y. Isocitrate dehydrogenase inhibitors in acute myeloid leukemia. Biomark Res 2019; 7: 22
8. Dear AE. Epigenetic modulators and the new immunotherapies. N Engl J Med 2016; 374: 684-6

Address for correspondence

Publication History

Received: 26 January 2020

Accepted: 27 May 2020

Article published online:
28 June 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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