Modulation of PPAR-Gamma Signaling in Prostatic Carcinogenesis.

摘要

The long term objective of this work is to elucidate metabolic pathways which can be used to reduce the need for radical surgery in patients at high risk for prostate cancer or with early stage disease. The hypothesis to be tested is that alterations to lipoxygenase (LOX) and cyclooxygenase (COX) activity in early prostate cancer represent distinct druggable pathways which can be treated in conjunction with the PPAR yamma signaling pathway to slow or prevent the development and progression of prostate cancer. In this final report we summarize the work performed over the life of the grant with details limited to the no cost extension period. We demonstrated the loss of PPAR yamma in a prostatic conditional knockout model. We showed that the combination of PPAR yaama loss with other common genetic insults can cause progression to a PIN phenotype, and that PPAR yamma loss in human epithelial cells results in phenotypic changes including both PIN and urothelial differentiation. We have demonstrated that changes in 15-lipoxygenase-1 and -2 expression can elicit changes in prostatic morphology, specifically premalignant lesions, as initially proposed. These findings validate the potential for chemopreventive uses for PPAR yamma agonists. During the life of the grant unexpected side effects of the TZD PPAR yamma agonists resulted in the withdrawal of these drugs from the market. We are investigating this as well as clinical links between TZD use and prostatic disease under funding from NIH. Results from the studies under this DOD-PCRP grant suggest the need for a new class of drugs to activate PPAR yamma for use in prostate cancer chemoprevention.