Epigenetic therapy in gastrointestinal cancer: the right combination

Abstract

Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer.

Keywords: CIMP; DNMT inhibitor; HDAC inhibitor chemosensitization; colorectal cancer; epigenetic therapy; gastrointestinal cancer; immune therapy; radiosensitization.

Figure 1.

The landscape of epigenetic modification of chromatin. Chromatin is composed of deoxyribonucleic acid (DNA) coiled twice around a set of eight histone proteins, forming a nucleosome. This is the fundamental subunit of chromatin. Promoter hypermethylation of DNA at CpG islands causes a condensed heterochromatin structure that silences transcription of genes. Demethylation and acetylation at histone lysine tails contributes to an open euchromatin conformation that is amenable to binding by the transcription machinery of the cell. Methylation at histone lysine tails also influences gene transcription, but these marks can be either repressive or activating depending on which lysines of which histone proteins are methylated. Repressive histone lysine methylation marks interact with proteins that make up the polycomb repressive complex that can interact with multiple genes and nucleosomes to repress gene transcription. Some of these genes are bivalent and can quickly revert from a repressed to an active state. Noncoding RNAs can interact with genes to either silence or activate transcription. Ac, acetylation of histone lysines, lavender circles on histone tails; Me, methylation of histone lysines, green circles on histone tail; DNA, deoxyribonucleic acid; DNA methylation, red circles on heterochromatin; PRC, polycomb repressive complex; P, phosphorylation, light blue circles on histone tail; RNA, ribonucleic acid.