P01.07.A ESTABLISHING A SCREENING PLATFORM ON PATIENT-DERIVED ORGANOIDS TO IDENTIFY EFFECTIVE AGENTS TO TREAT GLIOBLASTOMA

Abstract BACKGROUND Despite aggressive treatments, encompassing surgery, radiotherapy, and chemotherapy, glioblastoma (GBM) presents with poor prognosis and regular recurrence. To improve outcome for recurrent GBM, we established a translational pipeline using patient-derived organoids (PDOs) to test promising agents ex vivo. By evaluating drug responses in PDOs, we capture inter- and intratumoral heterogeneity and aim to identify the most effective agents for treating GBM in personalized treatment strategies. MATERIAL AND METHODS An extensive literature review identified nine drugs with distinct modes of action that have been used in compassionate use programs or Phase III studies. The drugs’ IC50 was initially determined in 2D cell lines and subsequently verified with PDOs. PDOs of n = 3 different patients as well as 6 different regions of one tumor were treated with the drug panel for 7 days. On day 8, intra- as well as intertumoral heterogeneity of cell viability was quantified using the alamarBlue assay, and apoptosis assessed by CC3 immunofluorescence staining. RESULTS Significant inter- and intratumoral differences in PDO-response to the drug panel were detected. Crizotinib (pintertumoral = 0.0002, pintratumoral = 0.0255), Fimepinostat (pintertumoral < 0.0001, pintratumoral = 0.0006) and Sunitinib (pintertumoral < 0.0001, pintratumoral = 0.0092) resulted in significant inter- as well as intratumoral differences in response to treatment. Nilotinib (pintertumoral = 0.0009), Dasatinib (pintertumoral = 0.0046), Sorafenib (pintertumoral = 0.0096) and Rapamycin (pintertumoral < 0.0001) showed intertumoral heterogeneity only. Last but not least, Selumetinib (pintratumoral = 0.0001) triggered significant intratumoral differences. CONCLUSION Our findings support the use of PDOs as a promising ex vivo platform to model inter- and intratumoral heterogeneity and assess drug response in GBM. This study serves as a proof of concept for integrating drug panel testing into PDO-based workflows, highlighting its potential value for molecular tumor board decision-making. The observed variability in treatment response across tumor regions and patients underscores the need for personalized therapeutic strategies. Future studies should expand this approach to larger patient cohorts and incorporate integrated genomic and transcriptomic analyses to fully interpret drug response patterns and refine individualized treatment predictions.