Biological rationale for the use of PPAR/agonists in glioblastoma

Glioblastoma multiforme (GBM) is the most common primary intrinsic central nervous system tumor and has an extremely poor overall survival with only 10% patients being alive after 5 years. There has been interesting preliminary evidence suggesting that diabetic patients receiving peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, a group of anti-diabetic, thiazolidinedione drugs, have an increased median survival for glioblastoma. Although thiazolidinediones are effective oral medications for type 2 diabetes, certain agonists carry the risk for congestive heart failure, myocardial infarction, cardiovascular disease, bone loss, weight gain, and fluid retention as side-effects. The nuclear receptor transcription factor PPAR gamma has been found to be expressed in high grade gliomas, and its activation has been shown to have several antineoplastic effects on human and rat glioma cell lines, and in some instances an additional protective increase in antioxidant enzymes has been observed in normal astrocytes. At present, no clinical trials are underway with regards to treating glioma patients using PPAR gamma agonists. This review presents the case for evaluating the potential of PPAR gamma agonists as novel adjuvants in the treatment of refractory high grade glioma.