MBRS-09. EphA3 A NOVEL TUMOUR SPECIFIC THERAPEUTIC TARGET FOR MEDULLOBLASTOMA

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2018-06, Vol.20 (suppl_2), p.i130-i130
• Main Authors: Offenhauser, Carolin, Carrington, Benjamin, Thurecht, Kris, Ensbey, Kathleen, Bruce, Zara, Jamieson, Paul, Lim, Yi Chieh, Akgul, Seckin, Li, Michelle, Stringer, Brett, Puttick, Simon, Fuchs, Adrian, Picard, Daniel, Ingram, Wendy, Hallahan, Andrew, Moore, Andrew, Johns, Terrance, Gottardo, Nicholas, Remke, Marc, Boyd, Andrew, Day, Bryan
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noy059.454

Abstract Targeted tumour specific therapies for children with medulloblastoma are required to improve survival and reduce the significant long-term side effects associated with current treatment protocols. Our study identifies the receptor tyrosine kinase EphA3 as a tumour specific novel therapeutic target for medulloblastoma and demonstrates safety and efficacy of EphA3-targeting antibody-drug conjugates (ADCs) in preclinical primary medulloblastoma xenograft models. Analysis of published medulloblastoma gene expression datasets shows a significant proportion of medulloblastoma samples across all subtypes have elevated expression of EphA3. Immunohistochemistry staining confirmed positive EphA3 expression in medulloblastoma specimens particularly in the perivascular region, a known stem cell niche. Thus, to target EphA3 in medulloblastoma we developed EphA3-ADCs by conjugating our EphA3-targeting monoclonal antibody IIIA4 to the tubulin-inhibitor maytansine. These EphA3-ADCs were highly effective in vitro and, more importantly, showed significant anti-tumour activity while being well tolerated in vivo in primary orthotopic xenograft models of medulloblastoma. Using intravital bioluminescence imaging we found that treatment with EphA3-ADCs reduced tumour burden of established tumours and, as a corollary, significantly improved survival of these tumour-bearing mice, with a commensurate drop in EphA3 tumour expression levels. We propose that combining EphA3-ADCs with current treatment modalities has the potential to improve outcome and may allow de-escalation of current therapies.