CBMT-28. FATTY ACID OXIDATION PROVIDES METABOLIC PLASTICITY TO MAINTAIN GROWTH IN THE DYNAMIC MICROENVIRONMENT OF GLIOBLASTOMA

Abstract

Abstract Glioblastoma represents an aggressive, primary brain tumor with limited treatment options. Despite advances in molecularly characterizing glioblastoma, metabolic alterations driving its aggressive phenotype are only beginning to be recognized. Integrative cross-platform analyses coupling global metabolomic and gene expression profiling identified alterations in fatty acid β-oxidation (FAO) as a key metabolic node differentiating glioblastoma from low-grade astrocytoma, which was defined by an accumulation of acylcarnitines. Metabolic heterogeneity was observed within glioblastoma that could further define tumors as FAO ‘high’ and ‘low’, which were enriched with mesenchymal and proneural subtypes of glioblastoma, respectively. These findings were metabolomically and functionally recapitulated in molecular subtype-specific preclinical models, with the majority of baseline mitochondrial oxygen consumption being a result of enhanced FAO in these cells. The biologic consequence of enhanced FAO in glioblastoma is directly dependent upon tumor microenvironment. FAO serves as a metabolic cue to drive proliferation in a β-HB/GPR109A/cAMP-dependent autocrine manner in nutrient favorable conditions while providing an efficient, alternate source of ATP only in nutrient unfavorable conditions. Accordingly, inhibiting FAO alone in glioblastoma cells with etomoxir only led to modest anti-proliferative activity and minimal cytotoxicity. However, rational combinatorial strategies designed to target the dynamic roles FAO plays in gliomagenesis resulted in metabolic synthetic lethality in glioblastoma. Specifically, dual targeting of FAO (etomoxir) and glycolysis (2DG) resulted in robust energetic stress, necroptosis mediated cell death, and a significant improvement in survival in an orthotopic glioblastoma mouse model. In summary, we identified FAO as a dominant metabolic node in glioblastoma that provides metabolic plasticity, allowing these cells to adapt to their dynamic microenvironment. Combinatorial strategies designed to target these diverse roles FAO plays in gliomagenesis offers therapeutic potential in glioblastoma.