Targeting Cancer Cell’s Metabolism for Treatment of Human Malignant Glioma

Findings of our previous works have provided the general concepts associated with therapeutic strategies that target tumor cell energy metabolism. Our perspective is based on emerging evidence that glioma can be managed through metabolic normalization. The central hypothesis of this is that enhanced glucose uptake or decreased mitochondrial energy metabolism by HIF-1a may be used as therapeutic targets, which results in suppressing cell proliferation or inducing anoikis in malignant gliomas (Aim #1). However, upon glucose deprivation, cells may shift their metabolic networks or recycle nutrients for adaptation and survival. Glutamine is selectively used by rapid growing cancer cells to replenish TCA cycle (anaplerosis) and supply of metabolic intermediates. Blockade of glutaminolysis (Aim #2a) or reductive carboxylation (Aim #2b) to perturb these adaptive biochemical networks may act as complement cytotoxic agents in targeting malignant gliomas5 metabolism. Moreover, de novo phospholipid synthesis is required for cell membranes of rapid growing cancer cells, and thus inhibition of lipid synthesis (Aim #3) is another effective approach for managing malignant gliomas. Our specific aims are: Specific aim (I): To investigate whether targeting HIF-1a alters aerobic glycolysis and flux of TCA cycle in malignant glioma cells. To explore agents that suppresses HIF-1a protein levels and hence the protein expression and phosphorylation that regulate aerobic glycolysis (Warburg effect) and oxidative phosphorylation through TCA cycle. Our preliminary data revealed that treatment with camptothecin, fenofibrate, a-lipoic acid or ferrous glycinate suppressed HIF-1a protein levels in U87 glioma cells. Specific Aim (II): To examine whether inhibition of glutaminase by Bis-2-(5-phenylacetamido-1,2-4-thiadiazol -2-yl)ethyl sylfide (BPTES) or reductive carboxylation by oxalomale, would regulate cell proliferation, induce anoikis, affect the capability of cell invasiveness, and suppress cancer stem cell proliferation and survival in malignant glioma cells. Specific Aim (III): To determine whether lipid metabolism may be targeted for glioma therapy. We previously shown that fenofibrate, a-lipoic acid, or monacolin exerts lipid lowering effects in C2C12 myotube and hepatocytes. We will examine whether these lipid lowering agents affect glioma cell replication. We will also investigate whether combination of these lipid-lowering agents with agents that targets HIF-1a (Aim #1) or glutamine-dependent anaplerosis (Aim #2) in human glioma cells exert synergistic effect in suppression glioma cell replication in vitro and tumor progression in vivo.