The nuclear receptor PPAR gamma is a dominant regulator of adipose differentiation and a modulator of the growth of many cell types. It is activated by synthetic ligands including the synthetic thiazolidinedione (TZD) drugs, such as rosiglitazone. Recent data, from our lab and others, indicates that PPAR gamma activation can inhibit the growth of epithelial cells from prostate, breast and colon, and change patterns of gene expression toward a more differentiated phenotype. Small clinical trials in human prostate cancer have shown that rosiglitazone can cause a prolonged stabilization in PSA levels in a subset of human patients. This has led to an additional, larger clinical trial; this project is intended to help support and advance the planning and interpretation of human clinical trials for the use of PPAR gamma ligands in CaP.
Our first Aim will perform transcriptional profiling in human CaP cells treated with PPAR gamma ligands. We will pay particular attention to genes, which encode cell surface or secreted proteins, as these could serve to measure PPAR gamma activation.
Our second Aim will study the genetic status of the PPAR gamma gene in the patients in the DF/HCC clinical trials. In particular, it will be important to correlate responsiveness in the patients with expression levels and potential mutations or deletions in PPAR gamma.
Our final Aim will perform experiments in mice that will model the treatment of CaP with PPAR gamma ligands. We will first examine the effects of PPAR gamma, mutations on the propensity toward CaP in mice with mutations in PTEN and P21. These mice will then be used to examine the effects of a PPAR gamma ligand (rosiglitazone) before and during the development of cancer. These studies together will provide useful knowledge that may eventually lead to new methods to prevent or treat human CaP.
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