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Membrane proteomic profiling to identify candidate therapy targets for glioblastoma infiltration
Harry Porter1, Kayley Mulhall1, Maria Shah1
1Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK.
Background:
Glioblastoma (GBM) is an aggressive brain tumor characterized by rapid growth and infiltration. New therapies are desperately needed to improve GBM patient outcomes. Intra-tumoral heterogeneity is a common driver of failure for novel GBM treatments, and many preclinical studies rely on cell lines established from the tumor core. As a result, they fail to characterize the infiltrative tumor cells, which remain post-surgery and ultimately drive tumor recurrence.
Methods:
This study characterizes the membrane proteome of 3 patient-derived GBM cell lines isolated from the tumor invasive margin (GIN8, GIN28, and GIN31), which is a proxy for residual disease post-surgery. We combined plasma membrane protein analysis with total protein analysis using liquid chromatography-mass spectrometry to uncover therapeutic targets most amenable for drug repurposing. Molecular docking analysis predicted specific binding pockets on the surface of key membrane proteins against which the top 10 approved drug candidates were screened based on their binding energy scores.
Results:
Membrane proteins such as EDIL3, DYSF, ROBO1, SERPINE2, LOXL1, and CD70 were consistently significantly upregulated across GBM cell lines relative to healthy astrocyte controls, indicating potential functional roles in GBM progression. Molecular docking identified nilotinib (targeting LOXL1) and darifenacin (targeting SH3KBP1) as candidate drugs that can bind to identified membrane proteins. Nilotinib and darifenacin produced average IC50 values of 8.45 µM and 46.77 µM, respectively, in cell viability assays against GIN cell lines.
Conclusions:
These findings suggest that targeting membrane proteins offers promise for developing effective GBM therapies predicated on the most prognostically relevant intra-tumor region.
Insights
This study identified key membrane proteins in glioblastoma (GBM) invasive cells and found that approved drugs nilotinib and darifenacin show potential for repurposing as GBM therapies targeting these proteins.
Area of Science:
- Neuro-oncology
- Proteomics
- Drug Discovery
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with high recurrence rates.
- Intra-tumoral heterogeneity contributes to treatment failure.
- Current preclinical models often neglect infiltrative GBM cells, crucial for recurrence.
Purpose of the Study:
- To characterize the membrane proteome of patient-derived GBM invasive margin cell lines.
- To identify potential therapeutic targets for drug repurposing in GBM.
- To evaluate approved drug candidates against identified GBM targets.
Main Methods:
- Utilized liquid chromatography-mass spectrometry for plasma and total protein analysis.
- Isolated and analyzed 3 patient-derived GBM cell lines from the invasive margin.
- Performed molecular docking to screen approved drugs against surface membrane proteins.
Main Results:
- Identified significant upregulation of membrane proteins (e.g., EDIL3, ROBO1, LOXL1, CD70) in GBM cells versus astrocytes.
- Nilotinib (targeting LOXL1) and darifenacin (targeting SH3KBP1) showed binding affinity to identified proteins.
- Nilotinib and darifenacin demonstrated efficacy in GBM cell viability assays (IC50 values provided).
Conclusions:
- Targeting membrane proteins in the invasive region of GBM offers a promising therapeutic strategy.
- Drug repurposing of nilotinib and darifenacin shows potential for treating GBM.
- Focusing on residual disease post-surgery could improve GBM patient outcomes.
