Evaluation of molecular profiling platforms in clinical pharmacology

Doorn, M.B.A. van (2007)

Doctoral Thesis

In the studies comprising this thesis we evaluated the potential usefulness of cDNA microarray based gene expression profiling and 1H-NMR based metabolomics platforms as tools for the evaluation of novel PPAR_ and -_ agonists in future clinical __proof of concept studies__. We investigated the effects of rosiglitazone, (prototype PPAR_ agonist ) and ciprofibrate (prototype PPAR_ agonist) on global (target) tissue gene expression profiles and endogenous urinary and plasma metabolites of type 2 Diabetes Mellitus (T2DM) patients and healthy volunteers (HVs).The results from the transcriptomic analyses indicated that none of the genes in any of the tissues in either study group displayed a significant treatment response with either rosiglitazone of ciprofibrate vs. placebo at Bonferroni adjusted values and _=0.05. The results of the metabolomic analyses revealed significant rosiglitazone and ciprofibrate induced changes in endogenous urinary and plasma metabolite profiles of T2DM patients but not in HVs. We conclude that from the two molecular profiling platforms evaluated in this thesis, metabolomics currently appears to be the most promising platform for future application in clinical __proof of concept__ studies with novel PPAR agonist compounds in T2DM patients.In the studies comprising this thesis we evaluated the potential usefulness of cDNA microarray based gene expression profiling and 1H-NMR based metabolomics platforms as tools for the evaluation of novel PPAR_ and -_ agonists in future clinical __proof of concept studies__. We investigated the effects of rosiglitazone, (prototype PPAR_ agonist ) and ciprofibrate (prototype PPAR_ agonist) on global (target) tissue gene expression profiles and endogenous urinary and plasma metabolites of type 2 Diabetes Mellitus (T2DM) patients and healthy volunteers (HVs).The results from the transcriptomic analyses indicated that none of the genes in any of the tissues in either study group displayed a significant treatment response with either rosiglitazone of ciprofibrate vs. placebo at Bonferroni adjusted values and _=0.05. The results of the metabolomic analyses revealed significant rosiglitazone and ciprofibrate induced changes in endogenous urinary and plasma metabolite profiles of T2DM patients but not in HVs. We conclude that from the two molecular profiling platforms evaluated in this thesis, metabolomics currently appears to be the most promising platform for future application in clinical __proof of concept__ studies with novel PPAR agonist compounds in T2DM patients.

• Biomarkers
• Clinical drug evaluation
• Fibrates
• Healhy volunteers
• Metabolomics
• Molecular profiling
• Proof of concept
• Thiazolidinediones
• Transcriptomics
• Type 2 diabetes mellitus

• All authors: Doorn, M.B.A. van
• Supervisor: Cohen, A.F.
• Co-supervisor: Burggraaf, J.; Hoogdalem, E.J.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2007-05-24