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Insights into novel emerging epigenetic drugs in myeloid malignancies.

ABSTRACT: Epigenetics has been defined as 'a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence' and several epigenetic regulators are recurrently mutated in hematological malignancies. Epigenetic modifications include changes such as DNA methylation, histone modifications and RNA associated gene silencing. Transcriptional regulation, chromosome stability, DNA replication and DNA repair are all controlled by these modifications. Mutations in genes encoding epigenetic modifiers are a frequent occurrence in hematologic malignancies and important in both the initiation and progression of cancer. Epigenetic modifications are also frequently reversible, allowing excellent opportunities for therapeutic intervention. The goal of epigenetic therapies is to reverse epigenetic dysregulation, restore the epigenetic balance, and revert malignant cells to a more normal condition. The role of epigenetic therapies thus far is most established in hematologic malignancies, with several agents already approved by the US Food and Drug Administration. In this review, we discuss pharmacological agents targeting epigenetic regulators.

SUBMITTER: Chandhok NS

PROVIDER: S-EPMC6685116 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Insights into novel emerging epigenetic drugs in myeloid malignancies.

Chandhok Namrata S NS Prebet Thomas T

Therapeutic advances in hematology 20190806

Epigenetics has been defined as 'a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence' and several epigenetic regulators are recurrently mutated in hematological malignancies. Epigenetic modifications include changes such as DNA methylation, histone modifications and RNA associated gene silencing. Transcriptional regulation, chromosome stability, DNA replication and DNA repair are all controlled by these modifications. Mutations in genes enc ...[more]

PMID: 31431820

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Project description:BackgroundOlder adults with myeloid malignancies are susceptible to treatment-related toxicities. Accelerated DNAm age, or the difference between DNA methylation (DNAm) age and chronological age, may be used as a biomarker of biological age to predict individuals at risk. In addition, cancer treatment can also lead to accelerated DNAm age. Exercise is a promising intervention to reduce or prevent functional, psychological, and cognitive impairments in older patients with myeloid malignancies, yet there is little evidence of the effects of exercise on DNAm age. We explored (1) the associations of accelerated DNAm age with physical, psychological, and cognitive functions at baseline; (2) changes in DNAm age from baseline to post-intervention; and (3) the associations of changes in accelerated DNAm age with changes in functions from baseline to post-intervention.MethodsWe enrolled older patients with myeloid malignancies to a single-arm pilot study testing a mobile health (mHealth) exercise intervention that combines an exercise program (EXCAP©®) with a mobile application over 2 cycles of chemotherapy (8-12 weeks). Patients completed measures of physical, psychological, and cognitive functions and provided blood samples for analyses of DNAm age at baseline and post-intervention. Paired t-tests or Wilcoxon signed rank tests assessed changes in DNAm ages, and Spearman's correlation assessed the relationships between accelerated ages and functions.ResultsWe included 20 patients (mean age: 72 years, range 62-80). Accelerated GrimAge, accelerated PhenoAge, and DunedinPACE were stable from baseline to post-intervention. At baseline, DunedinPACE was correlated with worse grip strength (r = -0.41, p = 0.08). From baseline to post-intervention, decreases in accelerated GrimAge (r = -0.50, p = 0.02), accelerated PhenoAge (r = - 0.39, p = 0.09), and DunedinPace (r = - 0.43, p = 0.06) were correlated with increases in distance walked on 6-min walk test. Decreases in accelerated GrimAge (r = - 0.49, p = 0.03), accelerated PhenoAge (r = - 0.40, p = 0.08), and DunedinPace (r = - 0.41, p = 0.07) were correlated with increases in in grip strength.ConclusionsAmong older adults with myeloid malignancies receiving chemotherapy, GrimAge and PhenoAge on average are stable after a mHealth exercise intervention. Decreases in accelerated GrimAge, accelerated PhenoAge, and DunedinPACE over 8-12 weeks of exercise were correlated with increased physical performance. Future trials assessing the effects of exercise on treatment-related toxicities should evaluate DNAm age. Trial registration Clinicaltrials.gov identifier: NCT04981821.

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Insights into novel emerging epigenetic drugs in myeloid malignancies.

Publications

Insights into novel emerging epigenetic drugs in myeloid malignancies.

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