Changing the field of carcinogenicity testing of human pharmaceuticals by emphasizing mode of action
van der Laan, J.W.
van den Hoorn, T.
van de Water, B.
Lifetime testing for carcinogenicity of pharmaceuticals in rodents has been a controversial issue since the start of the International Conference on Harmonisation in 1990. Since 2010 the debate reached a new level following the proposal that a negative outcome of carcinogenicity studies can be predicted based upon the findings of 6 months studies. In addition, the value of pharmacological mode of action (MoA) data for positive prediction has become apparent. Such predictions rest heavily on prior data and first-in-class compounds are difficult to evaluate in this way. Virtual waivers are rarely given to such compounds. We discuss here the utility of in vitro -omics approaches to identify involvement of signalling pathways in the mode of action of human pharmaceuticals that might bear relevance for prediction of carcinogenic properties. It is of particular significance that this approach to mode of action analysis would comprise human relevance, and would not relate solely to the prediction of carcinogenicity outcome in rats. Our ultimate aim is to establish in vitro fluorescent reporters in human cells where individual key events that are functionally relevant in the signalling programs that drive cell proliferation are integrated. This would allow the qualitative and quantitative evaluation of key event activation as a predictive tool for the determination of the intrinsic carcinogenic potential of compounds. In the first instance, this involves the nuclear hormone receptor-mediated tumor promotor activity (e.g. estrogen receptor signalling or peroxisome proliferator PPAR-gamma signalling), which are both current topics of debate. © 2017
To reference this document use:
RAPID - Risk Analysis for Products in Development
ELSS - Earth, Life and Social Sciences
Food and Nutrition
Mode of action
Current Opinion in Toxicology, 3, 55-61