BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma

SIMPLE SUMMARY: Ependymomas are the second most common paediatric brain tumour, and the 5-year survival rate remains no higher than 50%. Identifying new prognostic markers and targets for therapy in ependymoma is an important area of research. In this study, we demonstrate that brain lipid binding protein (BLBP, FABP7) is expressed in a sub-population of cells in ependymoma patient samples, consistent with it being a cancer stem cell marker. BLBP expression was associated with both significantly reduced event free survival and overall survival. BLBP can be functionally inhibited by PPAR antagonists, and we demonstrated that these antagonists can reduce ependymoma cell migration, invasion and chemo-resistance. The BLBP ligand docosohexanoic acid also attenuated these three hallmark characteristics of ependymomas, leading us to conclude that BLBP is not just a prognostic marker for poor ependymoma survival, but that it represents a druggable target in ependymoma therapy. ABSTRACT: Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker for ependymoma therapy resistance. BLBP protein expression correlated with reduced overall survival (OS) in patients from two trials (CNS9204, a chemotherapy-led infant trial—5 y OS 45% vs. 80%, p = 0.011—and CNS9904, a radiotherapy-led trial—OS 38% vs. 85%, p = 0.002). All ependymoma cell lines examined by qRT-PCR expressed BLBP, with expression elevated in stem cell-enriched neurospheres. Modulation of BLBP function in 2D and 3D assays, using either peroxisome proliferator activated receptor (PPAR) antagonists or BLBP’s fatty acid substrate docosahexaneoic acid (DHA), potentiated chemotherapy response and reduced cell migration and invasion in ependymoma cell lines. BLBP is therefore an independent predictor of poor survival in paediatric ependymoma, and treatment with PPAR antagonists or DHA may represent effective novel therapies, preventing chemotherapy resistance and invasion in paediatric ependymoma patients.