Epidrug Repurposing: Discovering New Faces of Old Acquaintances in Cancer Therapy.

Michel Montalvo-Casimiro,Vasti Thamara Juárez-González,Marco Antonio Meraz-Rodriguez,Rodrigo González-Barrios,Luis A Herrera,Cristian Arriaga-Canon

doi:10.3389/fonc.2020.605386

Abstract

Gene mutations are strongly associated with tumor progression and are well known in cancer development. However, recently discovered epigenetic alterations have shown the potential to greatly influence tumoral response to therapy regimens. Such epigenetic alterations have proven to be dynamic, and thus could be restored. Due to their reversible nature, the promising opportunity to improve chemotherapy response using epigenetic therapy has arisen. Beyond helping to understand the biology of the disease, the use of modern clinical epigenetics is being incorporated into the management of the cancer patient. Potential epidrug candidates can be found through a process known as drug repositioning or repurposing, a promising strategy for the discovery of novel potential targets in already approved drugs. At present, novel epidrug candidates have been identified in preclinical studies and some others are currently being tested in clinical trials, ready to be repositioned. This epidrug repurposing could circumvent the classic paradigm where the main focus is the development of agents with one indication only, while giving patients lower cost therapies and a novel precision medical approach to optimize treatment efficacy and reduce toxicity. This review focuses on the main approved epidrugs, and their druggable targets, that are currently being used in cancer therapy. Also, we highlight the importance of epidrug repurposing by the rediscovery of known chemical entities that may enhance epigenetic therapy in cancer, contributing to the development of precision medicine in oncology.

Highlights

Since the turn of the century, epigenetics has become an important research area in human diseases study, where genetic mutations have been classically understood as the main cause in the development of human pathologies [1]
Whether an epigenetic modification has a facilitating or inhibiting role in the gene expression depends on the chemical nature of the mark that is placed over the chromatin, and the type of modification that is set down on the proximal environment of these genes [3]
Due to current knowledge about these epigenetic mechanisms, the importance of this regulatory system has become more evident and it has led to the understanding that epigenetic alterations are some of the main mechanisms underlying many human diseases such as cancer, which arises through aberrant genetic and epigenetic alterations, both of which have a key role in malignant transformation, tumor progression and prognosis [4]

Summary

INTRODUCTION

Since the turn of the century, epigenetics has become an important research area in human diseases study, where genetic mutations have been classically understood as the main cause in the development of human pathologies [1]. Due to current knowledge about these epigenetic mechanisms, the importance of this regulatory system has become more evident and it has led to the understanding that epigenetic alterations are some of the main mechanisms underlying many human diseases such as cancer, which arises through aberrant genetic and epigenetic alterations, both of which have a key role in malignant transformation, tumor progression and prognosis [4]. Epidrug repurposing allows exploring a wide diversity of molecular combinations in multifactorial diseases such as cancer, where combinational epigenetic therapies are likely to be more effective than monotherapy to overcome chemotherapy resistance [9]. We will discuss the main mechanisms and elements involved in epigenetic alterations in cancer and its relevance in cancer therapy response

Background in Epigenetics

II III IV

Section 1. DNMT inhibitors Non-nucleoside Hydralazine analogs

Section 2. DNMT and HDAC Dual Inhibitors

Findings

CONCLUDING REMARKS