P01.11.A GENERATION OF INFILTRATIVE GBM MODELS TO STUDY THE PARTICIPATION OF THE PERITUMORAL AREA IN TUMOR RECURRENCE AND SEARCH FOR NEW THERAPEUTIC STRATEGIES.

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by poor prognosis and a high recurrence rate despite multimodal treatment. These recurrences often occur near the surgical site, implicating infiltrative tumor cells in disease progression. In addition, therapies are less effective in this area due to the preservation of the blood brain barrier (BBB), which limits drug penetration. Therefore, we believe that new therapeutic interventions targeting the peripheral GBM zone are necessary in order to improve patient survival. However, the periphery of GBMs remains poorly studied, as most research has focused on the tumor core. In recent years, our laboratory has performed an initial characterization of the cell types present in the peritumoral zone of a cohort of GBM patients. We have observed substantial variability between patients, as well as between different areas within the same patient, with a strong impact on tumor progression. Moreover, we have identified specific molecules and signaling pathways that appear to be involved in tumor recurrence. However, better mouse models are needed to fully replicate the behavior of infiltrative GBM cells and their microenvironment in order to test our hypotheses. Here, we describe the generation and characterization of several murine ex vivo and in vivo GBM infiltrative models. To this end, we implanted several mouse GBM cell lines into immunocompetent mice and selected the most invasive cells by isolating and growing GFP+ cells from the contralateral side. After several rounds of orthotopic implantation and selection, we obtained “super-invasive” GBM models, which were characterized both immunohistochemically and molecularly. We aim to identify potential inhibitors of the signaling pathways revealed by our previous bioinformatic studies and to test their ability to halt tumor growth within the infiltrative environment, either alone or in combination with conventional treatments (radiotherapy, chemotherapy or immunotherapy). Our ultimate goal is to provide preclinical evidence to advance the most promising candidates to clinical testing in GBM patients in the short to medium term.