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

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.

Figure 1

Epigenetic regulation of gene expression. Gene expression is controlled in the promoter regions by a combination of DNA methylation and chromatin configuration. In normal cells, gene expression is silenced by condensing chromatin, methylating (at cytosine) DNA and deactylating histones. By contrast, active genes are those with open nucleosome spacing around the transcription start site, are unmethylated and associated with acetylated histones. CpG islands that are rich in cytosine and guanine—and are typically unmethylated to promote gene expression—can be epigenetically silenced by hypermethylation in cancer. Adapted from Figueiredo, L. M. et al. Nat. Rev. Microbiol. 7, 504–513 (2009).

Figure 2

Epigenetic control is involved in all the hallmarks of tumour initiation and survival. Tumorigenesis, propagation and survival are maintained through a complex interplay of multiple cellular biological processes, all of which are regulated to an extent by epigenetic control of gene expression. Targeting one signalling pathway or biological function can result in compensatory modulation of other, off-target drivers of cell survival. Epigenetic therapy offers the ability to concurrently target, and reverse, multiple aberrant signalling pathways as well as the expected compensatory changes in other pathways.

Figure 3

Concurrent widespread changes in gene expression with epigenetic therapy. Anticancer efficacy of treatment with epigenetic-modulating agents is ssociated with widespread changes in gene expression that affect multiple biological processes. Gene expression is increased through direct reversal of epigenetic modifications of genomic DNA, whereas, for cancer-promoting genes, gene expression is reduced by the re-expression of their regulatory genes. Abbreviation: EMT, epithelial–mesenchymal transition.