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

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.

Identification and validation of a novel HOX-related classifier signature for predicting prognosis and immune microenvironment in pediatric gliomas

“…Ependymomas are the second most common type of malignant pediatric brain tumor. Forty percent of cases remain incurable, and the 5-year survival in infants with is only 40%-52% (Gajjar et al, 2014;Sabnis et al, 2021). Medulloblastoma is the highest degree of intracranial malignancy of the glioma.…”

In vitro and in vivo modeling systems of supratentorial ependymomas

“…Sabnis et al. identified a subpopulation of BLBP -expressing CSCs in pediatric EPN patients, that correlated with increased susceptibility to relapse or death ( 24 ). In this study, they investigated the ability to target and inhibit BLBP by PPAR (peroxisome proliferator-activated receptors) antagonists, utilizing the BLBP high expressed ST-EPN neurosphere cell line DKFZ-EP1NS ( 24 ).…”

“…identified a subpopulation of BLBP -expressing CSCs in pediatric EPN patients, that correlated with increased susceptibility to relapse or death ( 24 ). In this study, they investigated the ability to target and inhibit BLBP by PPAR (peroxisome proliferator-activated receptors) antagonists, utilizing the BLBP high expressed ST-EPN neurosphere cell line DKFZ-EP1NS ( 24 ). Investigators treated the ST-EPN spheres with PPAR antagonists and observed both a significant reduction of BLBP expression as well as reduced cell viability and migration, highlighting CSCs and its subsets as potential therapeutic targets to reduce tumor invasion and progression ( 24 ).…”

Evolving Diagnostic and Treatment Strategies for Pediatric CNS Tumors: The Impact of Lipid Metabolism

“…A combination of GSK126 and atorvastatin, a cholesterol biosynthesis inhibitor, showed good results in a murine DIPG model [173], and LXR-623, an agonist of LXR, has been found to be very effective in killing GBM cells in a xenograft model by depleting cholesterol levels [188]. Fatty acid uptake by pediatric ependymoma cells in a 3D spheroid has been also targeted using GW9662 through inhibiting the brainlipid-binding protein (BLBP or FABP7) gene expression [176]. In addition to molecules targeting lipid-related pathways, other drugs of a lipid nature are being investigated.…”