OS06.6A Inhibition of GBM invasion by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist Perampanel

Abstract BACKGROUND Extensive tumor cell invasion within the brain represents a major problem for effective treatment of glioblastomas (GBMs). The invasive processes can be divided into three types: Collective cell invasion, perivascular infiltration and single-cell invasion into the brain parenchyma. It has recently been shown that GBM cells have the ability to form synapses with neural cells pointing at an extensive communication network between brain cells GBM cells. This communication network can be mediated via the metabolites glutamine and glutamate both needed for GBM cell proliferation. In this context, it has been shown in preclinical models that Perampanel, an antiepileptic agent, functioning as non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, has an inhibitory effect on GBM growth. In order to delineate how Perampanel affects GBM invasion, we here utilised a highly characterized 3D GBM-brain organoid invasion model where single-cell invasion was studied in real-time following Perampanel treatment. MATERIAL AND METHODS A brain coculture model, consisting of rat brain organoids expressing various markers of the human adult brain, where confronted with GFP-labelled tumor cells. By using time-lapse confocal microscopy, we quantified single-cell invasion patterns and speed of invasion using two glioma stem cell models (GSCs; BG5 and BG7). RESULTS Perampanel treatment significantly reduces tumor cell invasion into the brain organoids with the strongest effect seen in the most invasive GBM (BG5). Here, the single-tumor cell invasion ratio was reduced by 72 % compared to the control group (p=0.0033). In contrast, collective cell invasion was reduced by 19 % (p=0.028). Statistical analysis was performed using an unpaired sample t-test. CONCLUSION The AMPA glutamate receptor antagonist Perampanel significantly inhibits GBM invasion, suggesting an important role of the glutamate-glutamine cycle between the GBM cells and neurons in the invasion process. Moreover, this communication and exchange of metabolites seems to be more prominent where single GBM cells invade into the brain parenchyma compared to areas where collective invasion take place.