CBMT-39. TARGETING METABOLIC PATHWAYS IN HYPOXIA FOR GLIOBLASTOMA

Abstract

Abstract BACKGROUND Metabolic adaptation to hypoxia is a crucial consideration in combating anti-angiogenic resistance. We previously explored the potential of targeting the peroxisomal fatty acid oxidation (FAO) pathway and observed higher potency to peroxisomal FAO inhibitor thioridazine in hypoxia in vitro. In this study we further examine the effects of peroxisomal FAO enzyme ACOX1, looking at differences in mitochondrial and peroxisomal FAO in hypoxia between subtypes, and explore additional metabolic pathways that can be potentially further studied. METHODS We utilized a CRISPR doxycycline-inducible U251 knockout cell line for the peroxisomal FAO gene ACOX1 and examined growth and viability in 2 weeks hypoxia (2% O2). We analyzed the gene expression of 13 peroxisomal and mitochondrial FAO enzymes in six different patient-derived cell lines. Finally, we characterized serum metabolites that are associated with tumor hypoxic volume, progression-free survival, and overall survival in patients undergoing clinical trial for TH302 and bevacizumab with bevacizumab refractory tumors. RESULTS We observed decreased cell growth and viability (p < .03) specifically in hypoxia but not normoxia with ACOX1 knock out. We saw some changes in gene expression (|ΔΔCt| >1) in hypoxia for all genes, which differed between cell lines. ACOX1 and CPT1A expression were strongly decreased (|ΔΔCt| >2) while ACADSB expression was strongly increased for the proneural cell line. ACOX1 expression was strongly decreased in our most thioridazine-sensitive cell line. ACOX2, ACADVL, CPT1A, CPT1C, and DECR2 expression were strongly increased in one of the proneural cell lines. Twelve polar metabolites were positively or negatively correlated (|r| >.4) with both hypoxic volume and either overall survival or progression-free survival. CONCLUSION Peroxisomal FAO and other metabolic pathways may be essential to target in order combat metabolic resistance during anti-angiogenic therapy. Better understanding differences in metabolism in different tumor environments will help determine which targets will be most therapeutically useful.