EPEN-08. PHARMACOGENOMICS REVEALS ERBB2 AS A THERAPEUTIC TARGET IN PRIMARY EPENDYMOMA CULTURES. (23rd April 2019)

• Record Type: Journal Article
• Authors: Pauck, David; Sarikaya-Seiwert, Sevgi; Marquardt, Viktoria; Paisana, Eunice; 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 21(2019)Supplement 2
• Page Start: ii78
• Page End: ii79
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.065
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Ependymoma represents the third most common brain tumor entity of childhood. Successful targeted treatment approaches especially for RELA fusion-positive supratentorial ependymomas and posterior fossa type A ependymomas, the two subgroups known to be associated with worst prognosis, have so far not been discovered. We set up a high-throughput drug screening (HTS) pipeline to evaluate therapeutic efficacy of established chemotherapeutic agents and novel anti-cancer compounds currently in phase III and IV studies (n=196) in primary ependymoma cultures (n=12). Assay miniaturization to 1536-well microplates emerged as a key feature to enable drug screening from smallest sample amounts. Primary cultures faithfully recapitulated DNA methylation changes and copy number profiles detected in the corresponding primary tumors. In addition, entity and subgroup affiliation were consistent using molecular neuropathology 2.0 based classification (MNP 2.0, Capper, D. et al., Nature, 2018). These results confirm that the (epi)genetic landscape is maintained in short-term primary ependymoma cultures. We revealed remarkable chemoresistance by comparing HTS data of ependymomas to other established pediatric brain tumor models (n=48) and normal tissue controls (n=3). Notably, we identified Neratinib, an irreversible ERBB2 inhibitor, as the most prominent candidate drug amongst multiple targeted therapeutics with its preferential antitumoral activity in a subset of ependymoma cases (n=5). To unravel the mechanism of action of Neratinib, RNA sequencing of treated and untreated ependymoma cell lines (n=3) was conducted demonstrating highly specific abrogation of ERBB2 signaling. In summary, our study demonstrates the feasibility of primary culture drug screening for pediatric brain tumors to identify novel therapeutic approaches. Specifically, we identified preferential antitumoral activity of Neratinib in ependymomas providing a novel therapeutic approach for a largely chemoresistant entity.