Year: 2018
Type: conference-abstract
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.
Source: Neuro-Oncology
Authors: Carolin Offenhauser, Benjamin Carrington, Kris Thurecht, Kathleen Ensbey, Zara Bruce, Paul Jamieson, Yi Chieh Lim, Seckin Akgul, Michelle Li, Brett Stringer, Simon Puttick, Adrian Fuchs, Daniel Picard, Wendy Ingram, Andrew Hallahan, Andrew Moore, Terrance Johns, Nicholas Gottardo, Marc Remke, Andrew Boyd, Bryan Day
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2809572271