P09.09.B TUMOR PHENOTYPE DETERMINES RADIOTHERAPY RESPONSE IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is one of the most challenging primary brain tumors to treat. Radiotherapy (RT), combined with the oral alkylating agent Temozolomide (TMZ), constitutes the standard of care following surgical resection. Although the Stupp protocol has slightly improved the prognosis of GBM patients, tumor remains nearly universal. In previous studies, we found that the mesenchymal (MES) GBM subtype responds better to TMZ compared to proliferative (PRO) tumors, particularly when treatment intervals are extended. In this study, we aimed to evaluate the effect of RT on different GBM phentoypes using in vitro, in vivo, and ex vivo models. MATERIAL AND METHODS We employed two mouse glioma models generated by retroviral expression of either EGFR-wt or EGFR-vIII in primary neural progenitors derived from p16/p19 knockout mice, representing MES and PRO subtypes, respectively. These cell lines were used for in vitro assays (1, 2 and 3 Gy) and in vivo RT experiments (three fractions of 3Gy). For in vivo studies, EGFR-wt and EGFR-vIII cells were injected into immunodeficient mice, which were subsequently irradiated at different intervals (1, 4, and 7 days). Additionally, patient-derived tumoroids were generated, irradiated with a single 10 Gy dose, and molecularly characterized to assess treatment response. RESULTS While both cell lines exhibited similar radiosensitivity in vitro, only PRO tumors responded to RT in the in vivo model and in patient-derived tumoroids. Expanding the interval between RT cycles did not enhance the antitumor effect. Molecular analysis of treated tumors allowed us to identify candidate molecules that may enhance the efficacy of RT in GBM. CONCLUSION Our results indicate that the GBM response to RT is influenced by the tumor´s molecular subtype, suggesting a key role for the tumor in mediating resistance. The use of patient-derived tumoroids provides a valuable tool to validate these findings and advance toward personalized treatment strategies based on tumor phenotype.