Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γAgonists

Abstract

Despite clinical promise, dual-acting activators of PPARαandγ(here termed PPARα+γagonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARαis invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγcan in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARαas well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γagonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARα+γagonist ragaglitazar, and the available literature about the role of PPARαandγin rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γagonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.