DDEL-23. Membrane proteomic profiling to identify candidate therapy targets for glioblastoma infiltration

Abstract Intra-tumoural heterogeneity is a common driver of failure for novel IDH-wildtype glioblastoma (GBM) treatments, and many preclinical studies rely on cell lines established from the tumour core. Therefore, they fail to characterise the residual infiltrative cells which remain post-surgery and ultimately drive tumour recurrence. We hypothesise that plasma membrane proteins on the surface of these infiltrative cells offer attractive targets for chemotherapeutic agents as they are most visible to circulating drugs. The membrane proteome of patient-derived GBM cell lines isolated from the tumour infiltrative margin (GIN8, GIN28, and GIN31), which are a proxy for residual disease post-surgery, were characterised. The identified membrane proteome was compared to that of the healthy astrocyte membrane proteome. Any proteins ubiquitously expressed on GBM invasive margin cells and not detectable on healthy astrocytes have the potential to reduce off target toxicity. We combined targeted plasma membrane protein with total protein using proteomics techniques to uncover potential therapeutic targets most amenable for drug repurposing. Eighteen membrane proteins including EDIL3, DYSF, ROBO1, SERPINE2, LOXL1 and CD70 were upregulated in the GBM cell lines when compared to astrocytes, indicating putative roles associated with GBM progression. Furthermore, nine of these ubiquitously upregulated proteins were undetectable in astrocyte cells. Analysis of correlation between protein abundance ratio and survival time in GBM clinical samples retrieved from the CPTAC study on cBioPortal showed that ROBO1, LOXL1 and DYSF conferred a negative correlation with survival, which suggests that these membrane proteins could exhibit a functional role in GBM survival and progression. These findings suggest that targeting membrane proteins offers promise for developing effective GBM therapies predicated on the most clinically accurate intra-tumour region. Future work utilises molecular docking techniques to identify suitable repurposed drugs against the membrane proteins observed.