Overarching therapeutic challenges and arachidonic acid metabolism as a novel target in glioblastoma

Glioblastoma (GBM) is an aggressive form of central nervous system tumors that can occur in the brain or spinal cord. GBM treatment is challenging with limited options with traditional surgery, radiation, and chemotherapy due to mutational heterogeneity, hypervascularity, and predominant hypoxia throughout the tumors. When used as monotherapy or combination therapies, treatments involving angiogenesis pathway-based, mutation-based, or immune-based therapies have shown limited success in decreasing the GBM growth and improving survival, warranting urgent attention in both clinic and laboratory. We have been actively investigating the arachidonic acid (AA) metabolism pathways, where cytochrome P450 4 (CYP4) family of enzymes can produce 20-hydroxyeicosatetraenoic acid (20-HETE) metabolite, a critical signaling eicosanoid contributing to therapeutic resistance. We have shown that 20-HETE can activate several intracellular protein kinases, proinflammatory mediators, and chemokines in GBM. This chapter is focused on understanding the role of the AA metabolic pathway in GBM with an emphasis on the CYP4A-20-HETE axis as a novel therapeutic target. We have also discussed all the effective investigational mechanisms on how 20-HETE can promote GBM refractoriness to available therapies and how its inhibition could sensitize the tumor for improved outcomes.