Cancer Epigenetics Drug Discovery and Development

Dear Colleagues,

Cancer can be defined as a genetic and epigenetic worldwide disease. Increasing evidence has shown the contribution of epigenetic alterations to cancer development. The epigenetic machinery interprets cell intrinsic and extrinsic signals and in a dynamic yet reversible process is recruited to specific genes to implement an ordered lineage-specifying program when a stem cell develops to a differentiated cell. Alterations in this epigenetic machinery (mutations or overexpression of many chromatin remodelers, DNA hypermethylation) lead to disruptions in normal development resulting in many pathologies, and particularly in cancer.

In some solid tumors, such as pediatric cancers, the rate of somatic mutations is lower compared with adult tumors. In this subset of tumors, epigenetic alterations have been demonstrated to play a key role in tumor initiation and progression, likely due to a lack of differentiation in the original precursors of cancer cells.

One of the main applications of the epigenetic drug discovery field is to identify targeted therapy which is less toxic for cancer patients. The parameters for an efficacious epigenetic drug are the following: high specificity, low toxicity, and IC₅₀ at low nM concentrations. Today, a major challenge is testing the latest generation of epigenetic enzyme inhibitors with improved stability and solubility, with lower IC₅₀, and reduced side effects. Given that many components of the epigenome are enzymes and potentially druggable, it is important to identify those that have the greatest impact on tumor cell growth and invasive capacity that are targetable by their relative inhibitors with the lowest IC_50. Unfortunately, the clinical application of epigenetic inhibitors in many cancer patients has been accompanied by important side effects. General toxicity, re-methylation, and lack of specificity have been observed.

This Special Issue focuses on the design and development of epigenetic drugs and on their mechanism of action in regulating tumorigenesis. It includes in-vitro- and in-vivo-based cancer models evaluating the mechanisms of action of epigenetic inhibitors on cancer; clinical investigations on the role of the epigenetic drugs on cancer risk, treatment, and survival; novel methodological approaches to enhance the stability and solubility of these compounds; and novel strategies to reduce the toxic effects. For this Special Issue, we invite original research articles and reviews related to the use of epigenetic probes in clinical settings for pediatric and adult cancer patients.

Dr. Veronica Veschi
Dr. Carol J. Thiele
Dr. Zhihui Liu
Guest Editors

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• Epigenetic probes
• Side effects and limits of epigenetic drugs
• Epigenetic drugs in clinical trials