Abstract 5467: Identification of possible new treatment options for rare pediatric CNS tumors using a panel of validated and characterized PDX models

Abstract Central nervous system (CNS) malignancies are the most frequent group of childhood solid tumors. While pediatric mortality due to CNS tumors has decreased over the past 40 years, however, there has been no significant change in brain and other CNS tumor mortality in children and adolescents since 2007*. Advances in research and innovative therapies are crucial to improving outcomes and reducing mortality. Collaborative efforts between researchers, healthcare professionals, and the pharmaceutical industry play a pivotal role in developing more effective treatments for these indications. One important piece in this endeavor is the availability of well characterized preclinical models for rigorous preclinical testing. In the framework of the ITCCP4 consortium (www. ITCCP4. eu) our group determined the pharmacological profile of ten orthotopically implanted pediatric brain tumor PDX models. The panel comprises amongst others four CNS-BCOR models, one ZFTA: : RELA ependymoma model and two models of PFA ependymoma. We tested the models in a single mouse trial format with 16 arms covering standard of care therapy including radiation as well as targeted agents. All tumors were intracranially implanted into immune-compromised NSG mice. Tumor load was determined using a fluorescence based in vivo imaging technology based on the lentiviral transient transduction of PDX cells with iRFP713 prior to implantation into the brain. In addition, body weight and neurological scoring were monitored to determine the overall condition of the animals. At the end of the study brain tissue was harvested and tumor load confirmed by immunohistochemistry. Vismodegib, a first in class inhibitor of the hedgehog signaling pathway, was the most efficacious treatment with a significantly extended overall survival (Log Rank, p 0. 001) and a reduced tumor load compared to untreated control arms. The effect was most prominent in the subclass of CNS-BCOR models leading to growth delay or stable disease. Several targeted agents such as Ipatasertib (AKT inhibitor), Idasanutlin (MDM2-antagonist) and standard of care such as Carboplatin and Radiotherapy induced stable disease as well but had no significant effect on overall survival. The positive results for Vismodegib, Ipatasertib as well as Idasanutlin will be validated in a smaller subset of models in a conventional set-up to confirm the current dataset. In summary, the single mouse trial format using intracranially implanted PDX models proved to be a feasible tool to identify most promising drug candidates for pediatric ependymoma. *Ostrom QT, Price M, Ryan K, Edelson J, Neff C, Cioffi G, et al. . CBTRUS statistical report: pediatric brain tumor foundation childhood and adolescent primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro-Oncology (2022) 24 (Supplement₃): iii1-38. Citation Format: Eva Oswald, Dorothee Lenhard, Kanstantsin Lashuk, Olivier Delattre, Didier Surdez, Johannes Gojo, Daniela Lötsch-Gojo, Walter Berger, Stefan Pfister, Julia B. Schueler. Identification of possible new treatment options for rare pediatric CNS tumors using a panel of validated and characterized PDX models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5467.