Speaker abstracts: S01: Introduction to the PPAR agonist: The issues

Abstract

Proxisome proliferation activating receptor (PPAR) agonists are a structurally diverse group of small molecules, which bind to one, or more, of three different “nuclear-hormone” receptors (termed, alpha, gamma or delta) thereby activating a multi-component signal-transduction cascade, which ultimately results in transcriptional regulation of genes that play a fundamental role in the metabolism of lipids and carbohydrates. Initially, thiozolidinedione compounds were identified as so-called “insulin sensitisers” – with therapeutic potential to treat patients with type 2 diabetes. Only subsequently was it discovered that their mechanism of action resulted from modulation of PPAR gamma receptors. Early hopes that PPAR modulators would become medicines for the treatment of a wide range of chronic diseases: such as diabetes, dyslipidaemia, neurological disease, inflammatory disease, proliferative or neoplastic disease – have not been realised. Because of concern about the carcinogenic potential of PPARs, Regulatory Agencies have effectively put the entire PPAR class on “partial clinical hold”, by requiring that carcinogenicity studies should have been completed and reviewed, before permission can be given to conduct clinical trials with a treatment duration of 6 months or longer. When tumours develop in rodents at an exposure level less than 10-fold above the level of human therapeutic exposure, a very careful risk:benefit analysis is necessary and, in some cases, further development may be halted. The goal of this session is to critically review data on mechanism(s) of rodent tumour development and to examine its likely human relevance.