Epigenetics of Most Aggressive Solid Tumors: Pathways, Targets and Treatments.

Abstract

Simple SummaryThe large amount of knowledge regarding epigenetic pathways has opened a broad range of treatments that provide hope for adult patients with highly aggressive forms of solid tumors. The most commonly used treatments for epigenic modifications are based on the specific inhibitors of DNA methyltransferases, azacitidine and decitabine (5-AZA-dC), and on histone deacetylases inhibitors, such as trichostatin A (TSA) or vorinostat (SAHA). However, many other compounds are under investigation, and some are being evaluated in clinical trials. In this review, we have extracted relevant information about epigenetic pathways and treatments that target epigenetic modifications in highly aggressive tumors, as a new hope for these patients.Highly aggressive tumors are characterized by a highly invasive phenotype, and they display chemoresistance. Furthermore, some of the tumors lack expression of biomarkers for target therapies. This is the case of small-cell lung cancer, triple-negative breast cancer, pancreatic ductal adenocarcinoma, glioblastoma, metastatic melanoma, and advanced ovarian cancer. Unfortunately, these patients show a low survival rate and most of the available drugs are ineffective. In this context, epigenetic modifications have emerged to provide the causes and potential treatments for such types of tumors. Methylation and hydroxymethylation of DNA, and histone modifications, are the most common targets of epigenetic therapy, to influence gene expression without altering the DNA sequence. These modifications could impact both oncogenes and tumor suppressor factors, which influence several molecular pathways such as epithelial-to-mesenchymal transition, WNT/β–catenin, PI3K–mTOR, MAPK, or mismatch repair machinery. However, epigenetic changes are inducible and reversible events that could be influenced by some environmental conditions, such as UV exposure, smoking habit, or diet. Changes in DNA methylation status and/or histone modification, such as acetylation, methylation or phosphorylation, among others, are the most important targets for epigenetic cancer therapy. Therefore, the present review aims to compile the basic information of epigenetic modifications, pathways and factors, and provide a rationale for the research and treatment of highly aggressive tumors with epigenetic drugs.