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Combining epigenetic drugs with other therapies for solid tumours — past lessons and future promise

Nature Reviews Clinical Oncology volume 17, pages 91–107 (2020)Cite this article

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Abstract

Epigenetic dysregulation has long been recognized as a key factor contributing to tumorigenesis and tumour maintenance that can influence all of the recognized hallmarks of cancer. Despite regulatory approvals for the treatment of certain haematological malignancies, the efficacy of the first generation of epigenetic drugs (epi-drugs) in patients with solid tumours has been disappointing; however, successes have now been achieved in selected solid tumour subtypes, thanks to the development of novel compounds and a better understanding of cancer biology that have enabled precision medicine approaches. Several lines of evidence support that, beyond their potential as monotherapies, epigenetic drugs could have important roles in synergy with other anticancer therapies or in reversing acquired therapy resistance. Herein, we review the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other forms of anticancer therapy, including chemotherapy, radiation therapy, hormone therapy, molecularly targeted therapy and immunotherapy. We provide a critical appraisal of the preclinical rationale, completed clinical studies and ongoing clinical trials relating to combination therapies incorporating epi-drugs. Finally, we propose and discuss rational clinical trial designs and drug development strategies, considering key factors including patient selection, tumour biomarker evaluation, drug scheduling and response assessment and study end points, with the aim of optimizing the development of such combinations.

Key points

  • The first generation of drugs targeting the epigenome (epi-drugs) were developed using a ‘one size fits all’ approach and proved to have disappointing efficacy in patients with solid tumours.

  • The potential of epi-drugs to modulate the sensitivity of tumours to other anticancer drugs and to overcome therapy resistance presents major new avenues of clinical investigation.

  • A new generation of epi-drugs, which were developed to be more specific for their targets and have promising activity in certain biomarker-selected populations, is now entering early phase clinical trials and are showing promising efficacy.

  • Epi-drug development should follow a precision-medicine approach, with further identification of robust predictive biomarkers for patient selection and subsequent implementation of this strategy in clinical trials.

  • Sequential treatment schedules and/or dosing at less than the maximum tolerated dose might improve the efficacy and tolerability of epi-drugs when used in combination with various other anticancer therapies.

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Fig. 1: Targeting the epigenome.
Fig. 2: Epi-drugs can enhance the activity of other anticancer therapies to counteract the hallmarks of cancer.
Fig. 3: Rationale for epi-drug combination, with examples of synergy or reversal of resistance mechanisms.
Fig. 4: Overview of ongoing clinical trials of epi-drugs in combination with other anticancer therapies.
Fig. 5: Challenges to successful epi-drug development and combination scheduling strategies.

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Acknowledgements

The work of D.M. is funded by an Institut National de la Santé et de la Recherche Médicale (INSERM) l’Institut Thématique Multi-Organisme Cancer (ITMO Cancer) grant. The work of D.J. is funded in part by the Fondation ARC pour la Recherche sur le Cancer and Labex DEEP. The work of G.A. is funded by grants from la Ligue Nationale Contre le Cancer (Equipe labellisée Ligue), l’Agence Nationale de la Recherche (ANR-11-LABX-0044 ‘DEEP’, ANR-10-IDEX-0001-02 ‘PSL’, ANR-12-BSV5-0022-02 ‘CHAPINHIB’, ANR-14-CE16-0009 ‘Epicure’, ANR-14-CE10-0013 ‘CELLECTCHIP’, ANR-16-CE15-0018 ‘CHRODYT’ and ANR-16-CE12-0024 ‘CHIFT’) and the H2020 European Research Council (ERC-2015-POC project 678563 ‘EPOCH28’ and ERC-2015-ADG- 694694 ‘ChromADICT’). The work of S.P.-V. is funded by the ATIP–Avenir INSERM Young Group Leader grant programme and the Sites de Recherche Intégrée sur le Cancer (SIRIC; INCa-DGOS-INSERM_12551 ‘SOCRATE-2’).

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  1. These authors contributed equally: Daphné Morel, Daniel Jeffery, Geneviève Almouzni and Sophie Postel-Vinay

Authors and Affiliations

  1. ATIP–Avenir Group, UMR981, INSERM (French National Institute of Health and Medical Research), Gustave Roussy Cancer Campus, Villejuif, France

    Daphné Morel & Sophie Postel-Vinay

  2. Nuclear Dynamics Unit — UMR3664, National Centre for Scientific Research, Institut Curie, Paris, France

    Daniel Jeffery & Geneviève Almouzni

  3. University Hospital Brussels, Brussels, Belgium

    Sandrine Aspeslagh

  4. Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Saclay University, Villejuif, France

    Sophie Postel-Vinay

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All authors made substantial contributions to all aspects of manuscript preparation. D.M. and D.J. contributed equally as co-first authors and G.A. and S.P.-V. contributed equally as co-supervisors.

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Correspondence to Geneviève Almouzni or Sophie Postel-Vinay.

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Competing interests

As part of the Drug Development Department (DITEP), S.P.-V. has been a principal/sub-investigator of clinical trials for Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer, Beigene, Bioalliance Pharma, Biontech, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharmaceutical, Clovis Oncology, Daiichi Sankyo, Debiopharm, Eisai, Exelixis, Forma, Gamamabs, Genentech, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, H3 Biomedicine, Hoffmann-La Roche, Incyte, Innate Pharma, Iris Servier, Janssen, Kura Oncology, Kyowa Kirin, Lilly, Loxo Oncology, Lytix Biopharma, MedImmune, Menarini Ricerche, Merck Sharp & Dohme-Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, PharmaMar, Pierre Fabre, Rigontec, Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Tioma Therapeutics, to-BBB Technologies BV and Xencor. S.P.-V. has received research grants from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche and Sanofi, as well as non-financial research support (provision of drugs) from Astrazeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Johnson & Johnson, Lilly, MedImmune, Merck, NH TherAGuiX, Pfizer and Roche. S.P.-V. has also received research funding from Boehringer Ingelheim, Merck and Roche for research projects unrelated to this manuscript. S.P.-V. has participated on advisory boards for Merck and has benefited from non-financial support for attending symposia (travel paid and congress registration) from AstraZeneca. D.M., D.J., S.A. and G.A. declare no competing interests.

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Morel, D., Jeffery, D., Aspeslagh, S. et al. Combining epigenetic drugs with other therapies for solid tumours — past lessons and future promise. Nat Rev Clin Oncol 17, 91–107 (2020). https://doi.org/10.1038/s41571-019-0267-4

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