Targeting epigenetic mediators of gene expression in thoracic malignancies

Our plain-English summary of Targeting epigenetic mediators of gene expression in thoracic malignancies, by D.S. Schrump (Biochimica et Biophysica Acta, 2012).

The study

• Author: D.S. Schrump
• Journal: Biochimica et Biophysica Acta
• Published: 2012;1819(7):836-45
• Type of article: Review
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Lung and esophageal cancers and malignant pleural mesotheliomas are highly lethal neoplasms that are leading causes of cancer-related deaths worldwide. Presently, limited information is available pertaining to epigenetic mechanisms mediating initiation and progression of these neoplasms. The following presentation will focus on the potential clinical relevance of epigenomic alterations in thoracic malignancies mediated by DNA methylation, perturbations in the histone code, and polycomb group proteins, as well as ongoing translational efforts to target epigenetic regulators of gene expression for treatment of these neoplasms. This article is part of a Special Issue entitled: Chromatin in time and space.

Copyright © 2012 Elsevier B.V. All rights reserved.

In plain English

This article was a review by one author. It reviewed published research on epigenetic changes, such as DNA methylation and changes to histone proteins and polycomb group proteins, in lung cancer, esophageal cancer and malignant pleural mesothelioma (MPM). It also covered drugs meant to target these changes and described unpublished and ongoing work from the author's group. Among the MPM studies it described, one by Christensen and colleagues of 70 MPM specimens found that methylation of six cell cycle genes correlated with asbestos body burden. Destro and colleagues reported shorter median survival after extra-pleural pneumonectomy in patients whose tumors showed methylation (16 vs. 35 months; p=0.06). Kemp and colleagues found over-expression of EZH2 in 85% of MPM, which correlated with shorter survival after potentially curative resections. Early drug trials described in the review included some MPM patients. They produced no objective responses, though some patients had periods of stable disease. The author concluded that epigenetic regulators are attractive targets but that such therapies may need prolonged use and combination with other treatments.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published laboratory and clinical studies, plus unpublished and ongoing work from the author's group
• Who was studied: No study population of its own; the review covered studies of lung cancer, esophageal cancer and malignant pleural mesothelioma (tumor specimens, cell lines and clinical trial patients)
• Exposure: Not an exposure study. The review covered epigenetic alterations (DNA methylation, histone modifications, polycomb group proteins) and drugs targeting them, such as the nucleoside analogs 5-azacytidine and 5-aza-2' deoxycytidine (DAC) and HDAC inhibitors such as depsipeptide (romidepsin), sodium butyrate and SAHA (vorinostat). Asbestos and tobacco smoke were mentioned only through cited studies.
• Main results:
  • A cited study (Christensen et al.) of 70 MPM specimens found a significant correlation between methylation status of six cell cycle regulatory genes and asbestos body burden, irrespective of gender, age or tumor histology
  • A cited study (Destro et al.) of 79 MPM patients found methylation of at least one of four genes in 30% of cases. Among patients undergoing extra-pleural pneumonectomy, those with DNA methylation had shorter median overall survival than those without (16 vs. 35 months; p=0.06).
  • A cited study (Fischer et al.) of serum DNA in MPM found that methylation of any single gene had no association with survival, but RAR-beta combined with RASSF1A or DAPK correlated significantly with decreased survival
  • A cited study (Kemp et al.) found over-expression of EZH2 in 85% of MPM and no EZH2 expression in normal pleura or peritoneum. Over-expression correlated significantly with diminished survival of MPM patients undergoing potentially curative resections.
  • The review cited reports that MPM occurs much more frequently in smokers, and experimental work in which cigarette smoke enhanced asbestos-mediated development of MPM in rodents
  • In a cited phase I trial of DAC in 35 patients (22 lung cancer, 4 esophageal cancer, 6 MPM), no objective responses were observed. Two lung cancer patients had prolonged stabilization of disease (more than 1 year).
  • In an ongoing NCI trial of sequential romidepsin and flavopiridol infusions, which included 4 MPM patients, no objective responses had been observed. Seven patients with refractory cancers had disease stabilization lasting 4 to more than 12 months.
• The authors' conclusion: The author concluded that considerable data suggest epigenetic regulators contribute to the initiation and progression of thoracic malignancies and are attractive targets for intervention. The author added that epigenetic therapies may need to be given for prolonged periods and combined with chemotherapy, molecularly-targeted agents or immunotherapy.
• Limitations the authors state:
  • The author stated that relatively limited information is available on epigenetic alterations in thoracic malignancies, and specifically on DNA methylation in MPM
  • The author stated that the clinical relevance of cancer-testis gene activation in MPM has not been established

Topics

Medical terms in this study, explained in our Lexicon: Esophageal Cancer, Pleural Mesothelioma, Neoplasm.

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