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Epigenetic therapy in non-small-cell lung cancer: targeting DNA methyltransferases and histone deacetylases

Frank P Vendetti1, Charles M Rudin

  • 1Johns Hopkins University, The Sidney Kimmel Comprehensive Cancer Center, David H. Koch Cancer Research Building 2, Room 562, 1550 Orleans Street, Baltimore, MD 21231, USA.

Expert Opinion on Biological Therapy
|July 18, 2013
PubMed
Abstract

Insights

Combinatorial epigenetic therapy using DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors shows promise for non-small-cell lung cancer. Lower doses of these agents can re-express tumor suppressor genes and improve treatment responses.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Therapeutics

Background:

  • Epigenetic dysregulation, including DNA methylation and histone acetylation, drives oncogenesis.
  • DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are key regulators of these epigenetic changes.
  • Aberrant epigenetic control is a significant focus in cancer therapeutic research.

Purpose of the Study:

  • To review epigenetic alterations in non-small-cell lung cancer (NSCLC).
  • To examine preclinical and clinical studies targeting epigenetic modifications in NSCLC.
  • To evaluate the efficacy of combinatorial epigenetic therapy in NSCLC.

Main Methods:

  • Review of recent preclinical and clinical studies on epigenetic modifications in NSCLC.
  • Analysis of DNMT inhibitors and HDAC inhibitors, particularly at lower doses.
  • Investigation of combination strategies for epigenetic therapy.

Main Results:

  • DNMT inhibitors at maximally tolerated doses are cytotoxic with suboptimal methylation effects.
  • Lower doses of DNMT inhibitors combined with HDAC inhibitors can re-express silenced tumor suppressor genes.
  • This combinatorial approach has shown major clinical responses and may enhance responsiveness to other therapies.

Conclusions:

  • Combinatorial epigenetic therapy demonstrates encouraging clinical activity in NSCLC.
  • Potential long-term effects of global epigenome modification strategies require further study.
  • Additional clinical investigation, including biomarker discovery, is warranted for this therapeutic approach.

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