METB-04COULD ALTERED FATTY ACID AND EICOSANOID METABOLISM PROVIDE NOVEL THERAPEUTIC TARGETS IN BRAIN TUMOURS?

Abstract

Glioblastoma(GBM) is the mostcommon and most malignant glioma of the central nervous system. Meningiomas derived from the arachnoid cap cells are less aggressive tumours but atypical and malignantmeningiomas have similar migratory, invasive and highly proliferative properties to that of GBMs and are also particularly difficult to treat. Recent investigations in our laboratory have focussed on the eicosanoid pathways present in gliomas and meningiomas. Techniques used include qRT-PCR, Immunohistochemistry, Western blotting, ESI-LC-MS/MS, GCMS and cell migration assays. We have identified several of the eicosanoids involved in the control of both cell proliferation and apoptosis in glioma cells. A strong relationship was found between prostaglandins of the E series and their receptors, and cell migration in GBM-derived cells. qRT-PCR analyses have identified mRNA's correlated with differences in survival in GBM patients. GCMS and ESI-LC-MS/MS analyses, to profile the fatty acids and eicosanoids present in primary brain tumours, have shown significant differences between tumour types and among tumour grades. High grade tumours have significantly altered HODE, HETE and HEPE contents in comparison with lower grade tumours. We are currently investigating the role of eicosanoids in the control of ABC transporters in glioma cells and primary brain tumours. The expression and activity of ABCB and ABCC transporters were altered by the presence of cyclooxygenase (COX) 1 and 2 inhibitors. The improved response to chemotherapeutic drugs found after interfering with eicosanoid production supports the hypothesis that altered eicosanoid metabolism could be an important approach to adjuvant therapy, which maylead to improvements in patient response to drug treatment in the future.