ET-20INTERFERING WITH GLIOBLASTOMA MULTIFORME METABOLISM TO COMPLEMENT THERAPEUTIC EFFECTS OF TEMOZOLOMIDE

Glioblastoma multiforme (GBM) is an aggressive malignant brain tumor that has a very poor prognosis. In fact, the average life expectancy at the time of diagnosis is approximately 1.2 years. The cells that make up GBM, like cells in other difficult-to-treat cancers, use available glucose at a very high rate (high rate glycolysis, also known as the Warburg effect). The cells also exhibit metabolic plasticity allowing the growing tumor to quickly adapt to available nutrient even under conditions of starvation. In fact, during stress or starvation, GBM utilize autophagy, a process whereby the tumor cell engulfs its own organelles to fuel its energetic needs. Taken together, these unique features of GBM metabolism suggest that GBM-specific metabolic pathways could serve as novel therapeutic targets for GBM. Thus, the advantages of metabolic targets as therapies are at least two-fold: (1) the cancer cell can no longer use an efficient strategy for energy production, and (2) metabolic disruption results in stresses that can alter the cell surface and potentially lead to recognition of the danger by immune cells from the tumor microenvironment. Temozolomide (TMZ), the current standard-of-care therapy for treating GBM, was designed to cause DNA damage, cell cycle checkpoint arrest, oxidative stress, and apoptosis. However, some GBM overcome TMZ treatment by activating DNA repair enzymes, such as the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) or poly-ADP-ribose polymerase (PARP). In this study, we address the possibility that combination treatment using TMZ to promote DNA damage combined with an inhibitor of GBM-specific energy strategies (that may be required for effective DNA damage repair) will potentiate the effectiveness of TMZ alone.