STEM-41. A SUBSET OF GBM BRAIN TUMOR STEM CELL LINES ARE UNIQUELY DEPENDENT ON GLUTAMINE METABOLISM FOR AMINO ACID SYNTHESIS

Abstract

Glioblastoma multiforme (GBM) is the most aggressive adult primary brain tumor. Despite a treatment regimen involving surgical resection, chemotherapy, and radiation, GBM patients have a median survival of approximately 15 months. This poor outcome highlights the need for improved therapeutic approaches for GBM patients. A subpopulation of cells that exhibit stem cell properties, termed brain tumor stem cells (BTSCs), are hypothesized to be the source of recurrence and resistance due to their inherent ability to resist treatment, invade into normal tissue, and re-populate a tumor. We have recently found that a subset of BTSC lines are uniquely dependent on glutamine metabolism for survival and maintenance of their stem cell properties. This dependence on glutamine differs from the more conventional view that cancer cells rely on increased glucose metabolism. Inhibiting glutamine metabolism in the sensitive subset of BTSC lines, by targeting the enzyme glutaminase (GLS) that deaminates glutamine to produce glutamate, results in decreased growth, viability, and self-renewal. We have found that inhibition of GLS decreases intracellular glutamate levels and leads to amino acid depletion. Replenishing the amino acid pool using bovine serum albumin rescues the decrease in BTSC growth following GLS inhibition. Intriguingly, the sensitive subset of BTSC lines have low expression of the glutamate transporter termed excitatory amino acid transporter 2 (EAAT2), limiting their glutamate uptake. We are exploring the relationship between reduced glutamate uptake and glutamine dependence; specifically, by asking whether GLS inhibition-resistant BTSC lines become glutamine-dependent after exposure to glutamate transport inhibitors. Taken together, our findings point to a unique dependence on glutamine metabolism for amino acid synthesis, in a subset of BTSC lines. Our long-term goal is to pursue this glutamine dependence as a novel therapeutic strategy to target the cells at the root of this aggressive and lethal disease.