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The future of epigenetic therapy in solid tumours—lessons from the past

Nature Reviews Clinical Oncology volume 10, pages 256–266 (2013)Cite this article

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Abstract

The promise of targeting epigenetic abnormalities for cancer therapy has not been realized for solid tumours, although increasing evidence is demonstrating its worth in haematological malignancies. In fact, true clinical efficacy in haematopoietic-related neoplasms has only become evident at low doses of epigenetic-targeting drugs (namely, inhibitors of histone deacetylase and DNA methyltransferases). Describing data from preclinical studies and early clinical trial results, we hypothesize that in using low-dose epigenetic-modulating agents, tumour cells can be reprogrammed, which overrides any immediate cytotoxic and off-target effect observed at high dose. We suggest that such optimization of drug dosing and scheduling of currently available agents could give these agents a prominent place in cancer management—when used alone or in combination with other therapies. If so, optimal use of these known agents might also pave the way for the introduction of other agents that target the epigenome.

Key Points

  • Evidence of the effects of epigenetic-modulating agents has revealed their dramatic consequences on cellular programming, in particular reversing stem-cell-like behaviour and chemoresistance

  • Treatment with epigenetic drugs affects multiple cell signalling pathways, including those regulating immune response and evasion, apoptosis, cell survival and DNA-damage repair

  • If used optimally, the widespread targets of these agents can be their greatest feature—cancer cells abnormally regulate many diverse pathways, which likely results in major therapeutic barriers

  • Previous research and clinical use of these agents might have been hampered because their effects were assessed too early and the doses used were too high

  • Lower doses of these agents results in less cytotoxicity to normal tissue, and should provide the added time and exposure needed for the 'reprogramming' effect of epigenetic therapy to become evident

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Figure 1: Epigenetic regulation of gene expression.
Figure 2: Epigenetic control is involved in all the hallmarks of tumour initiation and survival.
Figure 3: Concurrent widespread changes in gene expression with epigenetic therapy.

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Acknowledgements

A portion of the authors' work cited in this article was supported by grants from SU2C (Stand Up To Cancer), Waxman Foundation, Hodson Endowment and the NCI (National Cancer Institute) CA043318. The authors thank Kathy Bender for help with manuscript preparation and submission.

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  1. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, CRB1, 1650 Orleans Street Suite 541, Baltimore, 21287, MD, USA

    Nilofer Azad, Cynthia A. Zahnow, Charles M. Rudin & Stephen B. Baylin

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  1. Nilofer Azad
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  2. Cynthia A. Zahnow
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  3. Charles M. Rudin
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  4. Stephen B. Baylin
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Contributions

N. Azad and S. B. Baylin researched the data for the article and wrote the manuscript. All authors contributed to the discussion of the article's content. C. A. Zahnow and C. M. Rudin edited the manuscript before submission.

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Correspondence to Stephen B. Baylin.

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Competing interests

S. B. Baylin acts as a consultant for MDxHealth and is entitled (with Johns Hopkins University) to received royalty shares from the sales of the methylation-specific PCR (MSP) assay.

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Azad, N., Zahnow, C., Rudin, C. et al. The future of epigenetic therapy in solid tumours—lessons from the past. Nat Rev Clin Oncol 10, 256–266 (2013). https://doi.org/10.1038/nrclinonc.2013.42

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