Precision epigenetic therapies in oncology

Abstract

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.

Keywords: Cancer; Epigenetics; HPTMs; Metastasis; Prognosis; Solid tumours.

Fig. 1

Schematic representation of the nucleosome, which is composed of an octamer of core histones (H2A, H2B, H3 and H4), which are stabilised by Histone H1 and 145–147 bp of DNA. Multiple different enzymes have a role in the addition and removal of histone modifications, such as acetylation (yellow hexagon) and methylation (red star). Writers and erasers can modify histones by allowing for the addition or removal of histone tail modifications, and readers can translate these modifications, which allows for distinct cellular profiles [–18]

Fig. 2

Histone deacetylases (HDACs) facilitate the removal of acetyl groups from lysine residues, resulting in condensation of chromatin (heterochromatin) and therefore repressing gene transcription by preventing access of transcriptional machinery to the DNA. HDAC inhibitors (HDIs) induce acetylation, which results in an open chromatin state and increasing gene expression. On the other hand, histone acetyltransferases (HATs) relax the chromatin structure, allowing for active gene transcription (euchromatin) [–39]

Fig. 3

The polycomb repressive complex (PRC2) is responsible for the tri-methylation of Histone 3, at Lysine 27 (H3K27), which is associated with gene repression. The PRC2 complex has three Main subunits; the enhancer of zeste 2 (EZH2) which catalyses the addition of methyl groups to H3K27, the embryonic ectoderm (EED) which enhances this catalysis by recognising and binding to H3K27 and stabilising the PRC2 complex, and the suppressor of zeste 2 (SUZ12), which regulates the level of H3K27me3. EZH2 overexpression has been linked to the repression of tumour suppressor genes, and derepression of these genes has been identified in advanced cancers and metastasis. Therefore, components of the PRC2 complex have become popular targets for drug discovery, as abrogating H3K27me3 levels may allow for an inhibition of cell proliferation in cancer [–68]

Fig. 4

Precision epigenetics pipeline proposed for tailored patient selection for epigenetic therapies. Therapeutic selection should be used to identify HPTM inhibitors (HPTMi), such as tazemetostat, an EZH2i, and anti-cancer compounds (AC) that, when combined, have a synergistic or strongly additive relationship (red), such as HPTMi1 and AC3, compared to weakly additive (yellow), or antagonistic (green). Pre-treatment profiling and biological contextualisation should then be used to identify patients that have cancers with overexpression of HPTMS, using techniques such as ChIP-Seq or ATAC-Seq, which allows for the unique epigenome of each patient to be identified, and an appropriate combination treatment to be selected. At this stage, circulating levels of HPTMs should be correlated with intra-tumoral epigenetic activity. This will then lead to patient selection and dynamic monitoring (e.g. early identification of relapses via liquid biopsies