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Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARalpha + gamma Agonists
Martin B Oleksiewicz1, Jennifer Southgate, Lars Iversen
1Molecular Toxicology, Novo Nordisk A/S, 2760 Maalov, Denmark.
Abstract:
Despite clinical promise, dual-acting activators of PPARalpha and gamma (here termed PPARalpha+gamma agonists) 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 PPARalpha is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARgamma can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARalpha as well as PPARgamma, making it plausible that the urothelial carcinogenicity of PPARalpha+gamma agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARalpha+gamma agonist ragaglitazar, and the available literature about the role of PPARalpha and gamma in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARalpha+gamma agonists 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.
Insights
Dual-acting PPAR agonists show promise but cause rat urothelial cancer. A proposed mechanism involves combined receptor-mediated and cytotoxic effects, guiding development of safer compounds.
Area of Science:
- Pharmacology
- Toxicology
- Carcinogenesis
Background:
- Dual-acting agonists targeting Peroxisome Proliferator-Activated Receptors alpha and gamma (PPARα+γ) show clinical potential but face development challenges.
- High attrition rates are linked to toxicity, specifically carcinogenic effects in the rat urothelium.
- Both PPARα and PPARγ activation are independently associated with rodent carcinogenesis.
Purpose of the Study:
- To propose a mode of action hypothesis for PPARα+γ agonist-induced urothelial carcinogenicity in rats.
- To investigate the combined role of receptor-mediated and off-target cytotoxic effects.
- To inform the development of safer dual-acting PPAR agonist compounds.
Main Methods:
- Literature review on PPARα and PPARγ roles in rodent carcinogenesis.
- Analysis of mode of action data for the PPARα+γ agonist ragaglitazar.
- Formulation of a hypothesis integrating receptor-mediated and cytotoxic effects.
Main Results:
- Urothelial cells coexpress PPARα and PPARγ, suggesting a plausible mechanism for agonist-induced carcinogenicity.
- A hypothesis combining exaggerated pharmacology (receptor-mediated) and off-target cytotoxicity is proposed.
- Ongoing laboratory investigations aim to validate this mode of action.
Conclusions:
- The proposed mode of action hypothesis provides a framework for understanding rat urothelial carcinogenicity of PPARα+γ agonists.
- Understanding this mechanism is crucial for assessing human relevance and developing safer drug candidates.
- Development of rapid screening assays is a key objective to facilitate future drug development.
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