Epigenetic therapy in gastrointestinal cancer: the right combination

Abstract

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.

Gastric Cancer in the Era of Precision Medicine

“…Meanwhile, targeting epigenetic regulators such as methyltransferases, demethylases, and miRNAs for cancer therapy are also under investigation. One ongoing clinical trial will evaluate combination therapy with vorinostat (a histone deacetylase inhibitor) and radiotherapy in GC (ClinicalTrials.gov identifier: NCT01045538) 132 . Furthermore, integration of GC genotype and phenotype by using PDX and patient-derived organoid models promises to assist clinical trial design and personalized medicine strategies in the future 16, 106.…”

The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

“…As well as giving rise to the concept of epi-mutations, the sequencing of DNA methylation events, inter-joined as they are with the regulation of histone modifications, also justified development of DNMT inhibitors and the combination of epigenetic therapies that targeted both CpG methylation and repressive histone modifications [64,65]. …”

Septin 9 hypermethylation contributes to migration and resistance to drug treatments in colon cancer

“…In particular, multiple CpG-rich promoter regions were extensively studied over the last decade and associated the methylation content with effect on transcription [17,18]. Similar hypermethylation content was also previously identified in promoter regions of septin 9 and implicated for modulating expression in breast cancer cells [19].…”