P01.20.b Convergent Evolution of Tumor Progression in Glioblastoma Patients

Abstract BACKGROUND Glioblastoma is the most common malignant brain tumor and is associated with a dismal prognosis, with only about 5% of patients surviving five years post-diagnosis. The disease is marked by extensive inter- and intra-patient heterogeneity, often resulting in unpredictable therapeutic responses leading to recurrent status. To elucidate the mechanisms underlying glioblastoma aggressiveness and heterogeneity, we profiled therapeutic resistance and sensitivity to identify potential vulnerabilities that may drive tumor recurrence. MATERIAL AND METHODS The tumor tissues from primary and recurrence patients with glioma were used for patient-derived glioblastoma cell (PDC) isolation prepared by mechanical and enzymatic tissue dissociation. After short-term cultivation (approximately 7-14 days) under standard culture conditions, spheroids were dissociated into a single-cell suspension and subjected to drug screening using a high throughput screening platform. Dose response curve (DRC) fitting per drug was performed and the area under the curve (AUC) was evaluated. These AUC values were used to employe Bland-Altman plots to compare drug sensitivity for each compound between newly diagnosed and recurrent glioblastoma samples from the same patient, in order to assess consistency and identify shifts in therapeutic response. RESULTS Using PDCs from till now six individuals, we evaluated responses to anti-cancer compounds in matched primary and recurrent tumors from the same patients. Initial analyses of longitudinal tumor samples from two IDH (isocitrate dehydrogenase) wild-type glioblastoma patients displayed similar patterns of drug sensitivity and resistance in their recurrent tumors. Both exhibited sensitivity to Pexidartinib, and Pazopanib, and resistance to Panobinostat and Selinexor, suggesting a comparable tumor evolutionary trajectory across different individuals. CONCLUSION Notably, genomic alterations alone were insufficient to explain the observed convergent evolution in these two patients. The underlying drivers of these shared resistance patterns remain unresolved. Therefore, these analysis of these two patients undergoing standard-of-care treatment seems to reveal a striking convergence in evolutionary tumor trajectories. We are currently performing more in-depth analyses of additional patient samples and investigating the role of the tumor microenvironment to further elucidate the mechanisms driving tumor progression and treatment resistance.