医学
临床试验
药物开发
表观遗传学
生物标志物
精密医学
药品
癌症
生物信息学
肿瘤科
表观遗传疗法
药理学
内科学
DNA甲基化
病理
生物
基因表达
基因
生物化学
作者
Daphné Morel,Daniel Jeffery,Sandrine Aspeslagh,Geneviève Almouzni,Sophie Postel‐Vinay
标识
DOI:10.1038/s41571-019-0267-4
摘要
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.
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