EPEN-33. PHARMACOGENOMICS REVEALS SYNERGISTIC INHIBITION OF ERBB2 AND PI3K SIGNALING AS A THERAPEUTIC STRATEGY FOR EPENDYMOMA. (4th December 2020)

• Record Type: Journal Article
• Authors: Pauck, David; Paisana, Eunice; Cascão, Rita; Sarikaya-Seiwert, Sevgi; Marquardt, Viktoria; Picard, Daniel; Bartl, Jasmin; Blümel, Lena; Maue, Mara; Dimitriadis, Christian; Taban, Kübra; Fischer, Ute; Steiger, Hans Jakob; Faria, Cláudia; Reifenberger, Guido; Borkhardt, Arndt; Beez, Thomas; Remke, Marc
• Is Part Of: Neuro-oncology. Volume 22(2020)Supplement 3
• Page Start: iii314
• Page End: iii314
• Publication Date: 2020-12-04
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa222.168
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Subgroups of ependymoma, especially RELA fusion-positive and posterior fossa type A tumors, are associated with poor prognosis. Curative therapeutic strategies have not yet been identified. We set up a high-throughput drug screening (HTS) pipeline to evaluate clinically established compounds (n=196) in primary ependymoma cultures (n=12). As culturing ependymoma is challenging, assay miniaturization to 1536-well microplates emerged as a key feature to process HTS despite smallest cell numbers. DNA methylation profiling showed that entity and subgroup affiliation from primary diagnosis was maintained in primary cultures, as assessed through molecular neuropathology 2.0 based classification (MNP 2.0, Capper, D. et al., Nature, 2018). A comparison of HTS data of ependymoma and other pediatric brain tumor models (n=48) revealed a remarkable chemoresistance in vitro. However, we identified Neratinib, an irreversible ERBB2 inhibitor, as the most prominent candidate which was preferentially active in a subset of the investigated ependymoma cultures (n=5). Combinatory treatment with Copanlisib, a PI3K inhibitor, was able to overcome resistance to single agent treatment using Neratinib in established cell lines of ependymoma (n=3) and 2/4 primary cultures for which combinatory treatment could be tested. Finally, we validated efficacy of Neratinib combined with Copanlisib in mice bearing ependymoma xenografts which revealed significantly reduced tumor size compared to vehicle-treated animals. In summary, our study demonstrates that HTS may reveal targeted therapies for pediatric brain tumors. Specifically, we found a synergistic interaction of Neratinib and Copanlisib for treatment of ependymoma, thereby providing a novel therapeutic approach in an otherwise largely chemoresistant entity.