Polyamine and Glutamate Driven Interactions in the Glioblastoma-Brain Microenvironment

Project Summary Radiotherapy is a standard modality for brain lesions, and has led improvements in patient outcome through the addition of high precision stereotactic delivery and more recently particle therapy. While patients are benefiting from increasing survival times, cognitive complications develop with increased frequency and are thus challenging treatment paradigms. Biologically, the mechanisms of neurotoxicity from ionizing radiation are unclear. Recent studies have highlighted exquisite sensitivity to an organ that has been traditionally thought to be radioresistant due to its non-proliferative nature. Dendrite remodeling, neuroinflammation, and excitotoxicity are all elevated following exposure to ionizing radiation, and are thought to contribute to decreased cognition. In the current application, we propose that excessive glutamate signaling is a key driver of cognitive damage from radiation. In addition, our group has been investigating the role of the polyamine pathway in radiation resistance of tumor cells. Both glutamate and polyamines are found to be elevated in brain tumors, an induced secretion is evident after exposure to radiation. In mechanistic studies, we implicate the NMDAR NR2B subunit as a specific target of glutamate and polyamines that leads to neurotoxicity. We hypothesize that blocking glutamate-receptor signaling with a specific glutamate receptor antagonist will reduce CNS damage due to radiation, and sensitize tumor cells to radiation induced death, and therefore improve patient outcomes.