Abstract Aggressive ependymomas often recur within the irradiation field, indicating the presence of tumor cells highly resistant to radiotherapy. However, adjuvant treatments enhancing radiotherapy efficacy remain absent. To address this gap, we conducted radiation dose-determining experiments that confirmed high radioresistance across posterior fossa group A and ZFTA fusion-positive patient-derived ependymoma short-term organoid-like cultures and cell lines. To identify radiosensitizing drugs, we employed a combinatorial in vitro screening approach using a fractionated long-term irradiation protocol (15 daily doses of 1.8 Gy) in conjunction with a library of 137 clinically relevant drugs based on the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) drug sensitivity profiling, an international pediatric precision oncology program that enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis and clinically focused drug library-based sensitivity profiling. This screen consistently revealed increased sensitivity to several targeted agents, including BH3-mimetic drugs and histone deacetylase (HDAC) inhibitors, under irradiation conditions. In vitro validation combining the BCL-XL-specific BH3-mimetic A-1155463 or the HDAC-inhibiting anticonvulsant valproate with various irradiation schedules and dose intensities demonstrated increased radiation sensitivity, achieving synergistic effects at nanomolar doses of A-1155463 and at clinically achievable doses of valproate in 26-day combination treatments. Pilot experiments with orthotopic patient-derived xenograft ependymoma mouse models demonstrated irradiation-induced responses at tolerable transcranial doses. Ongoing in vivo studies aim to further preclinically validate the radiosensitizing potential of valproate and BCL-XL inhibition. These findings suggest the systematic exploration of valproate radiosensitization, currently used without irradiation in the SIOP EPN II trial, and highlight BCL-XL inhibition as a novel mechanism to enhance radiotherapy efficacy in ependymoma.
Bamberg et al. (Fri,) studied this question.