Can systems toxicology identify common biomarkers of non-genotoxic carcinogenesis?

Abstract

For the rapid development of safe, efficacious chemicals it is important that any potential liabilities are identified as early as possible in the discovery/development pipeline. Once identified it is then possible to make rational decisions on whether to progress a chemical and/or series further; one such liability is chemical carcinogenesis, a highly undesirable characteristic in a novel chemical entity. Chemical carcinogens may be roughly divided into two classes, those that elicit their actions through direct damage to DNA (genotoxic carcinogens) and those that cause carcinogenesis through mechanisms that involve direct damage of the DNA by the agent (non-genotoxic carcinogens). Whereas the former group can be identified by in vitro screens to a good degree of accuracy, the latter group are far more problematic due to their diverse modes of action. This review will focus on the latter class of chemical carcinogens, examining how modern '-omic' technologies have begun to identify signatures that may represent sensitive, early markers for these processes. In addition to their use in signature generation the role of -omic level approaches to delineating molecular mechanisms of action will also be discussed.