Glioblastomas are very aggressive tumors of the central nervous system (CNS) with a median patient survivalof about 16 months. Therapeutic options for glioblastoma patients are very limited mostly because the majorityof potential anti-cancer drugs do not cross the blood brain barrier (BBB). In addition, recently testedimmunotherapies including immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapies failed toproduce a positive outcome in glioblastoma patients. Surprisingly, metabolic approaches including calorierestriction and ketogenic diet demonstrate promising results as supplemental therapies for glioblastoma patients.In this regard, multiple studies, including our research, show that a common lipid-lowering prodrug, fenofibrate(FF), triggers a severe energetic crisis in glioblastoma cells by compromising the function of Complex 1 of theelectron transport chain (ETC), leading to the extensive glioblastoma cell death. However, FF does not cross theBBB and is quickly processed by blood and tissue esterases to fenofibric acid, which is a potent PPARµ agonist,no longer effective in killing glioblastoma cells. Therefore, we have made several chemical modifications in theFF molecular skeleton to construct a new family of drugs with high anti-glioblastoma potential. In this proposal,we attempt to test the overall hypothesis that specific chemical modification/s in the common molecular skeletonof FF, benzyl-phenoxy-acetamide (BPA), will result in a new anti-glioblastoma metabolic drug/s that are stable,capable of crossing the BBB, and effective in triggering glioblastoma cell death at low µM concentrations. Ourpreliminary results indicate that two new drug candidates designated here, as MT1 and MT3, have very promisingcharacteristics for BBB penetration. To evaluate these compounds, we have developed a comprehensiveexperimental approach consisting of: a) computational modeling of the BPA molecular structure by applying theCentral Nervous System - Multiparameter Optimization (CNS-MPO) algorithm; b) development of the mosteffective strategy for synthesis and testing of chemical integrity and purity of the new compound; c) in vitro testingfor glioblastoma cytotoxicity and the mechanism of action; and d) Pharmacokinetic analyses of the compoundbioavailability, maximal tolerated dose (MTD) and anti-glioblastoma efficacy in highly relevant animal models.
Public Health Relevance Statement: Glioblastomas are very aggressive and practically incurable brain tumors for which new treatments are
urgently needed. We are developing and testing a new class of metabolic drugs, which are based on a specific
chemical modifications of a common lipid lowering drug, fenofibrate. Testing their anti-glioblastoma efficacy in
highly relevant animal models and better underlying how the compounds work will set the stage for a new
metabolic approach in support of the existing and emerging anti-glioblastoma therapies.
Project Terms: | | | | 