Precision epigenetic therapies in oncology

Phenotypic plasticity is a key mechanism of metastatic progression and cancer therapy resistance. This hallmark of human malignancies is enabled by highly conserved epigenetic mechanisms that control gene expression. Functional alterations in DNA methylation and histone post-translational modifications have been extensively described as drivers of metastatic dissemination and therapy resistance. Pharmacological inhibitors of epigenetic enzymes can revert these alterations, thereby stopping cancer progression and counteracting the emergence of resistant clones. Despite promising pre-clinical evidence, the clinical implementation of epigenetic therapies in solid cancers has led to disappointing results. Several factors can explain these challenges, including the lack of rational combinations. Notably, response to epigenetic treatments can be heterogeneous and short-lived. A liquid biopsy technology that allows the measure of specific epigenetic alterations enables patient selection and therapy monitoring, leading to the development of precision epigenetic therapies. In this review, we discuss the state of the art of this emerging treatment modality, and we identify key challenges that need to be overcome to reach the full potential of this new therapeutic concept.