DNMT Inhibitors Increase Methylation in the Cancer Genome

In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients. Introduction DNA methyltransferase inhibitors (DNMTi) are widely used as chemical tools for hypomethylating the genome, with an aim to understand the role of DNA methylation in multiple processes (e.g., X-chromosome inactivation and DNA imprinting) and as an anti-cancer therapy (Minkovsky et al., 2015; Ramos M.P. et al., 2015; Bohl et al., 2018). At present, two DNMTi drugs, decitabine and azacytidine, have been approved for treating patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) (Döhner et al., 2017; Bohl et al., 2018), and are also being tested as therapeutic options in multiple solid cancers (Fu et al., 2011; Singal et al., 2015; Lee et al., 2018). However, treatment response rates have remained very low in both solid and hematological cancers patients (Derissen et al., 2013; Nervi et al., 2015; Koch et al., 2018). At the same time, DNMTi treatment incurs considerable side effects (e.g., bleeding, anemia, and joint pain). Attempts are being made to improve treatment efficacy (e.g., by testing combinations of DNMTis with other anticancer agents) and safety (e.g., by stratifying can...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research

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We describe the most highly recommended generic and disease-specific PRO tools in SCD and discuss the challenges of incorporating them in clinical practice. EXPERT OPINION: PRO measures are essential to incorporate into SCD clinical trials either as primary or secondary outcomes. The use of PRO measures in SCD facilitates a patient-centered approach, which is likely to lead to improved outcomes. Significant challenges remain in adapting PRO tools to routine clinical use and in developing countries. PMID: 33034214 [PubMed - as supplied by publisher]
Source: Expert Review of Hematology - Category: Hematology Tags: Expert Rev Hematol Source Type: research
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