Abstract 3474: Integrative metabolomic and genomic analysis identifies fatty acid oxidation as a metabolic node in glioblastoma

Abstract

Abstract Glioblastoma (GBM) represents an aggressive brain tumor with limited treatment options. Although considerable progress has been made in understanding molecular alterations unique to these tumors, the diverse metabolic programs driving their aggressive phenotype are only beginning to be recognized. As an initial investigation, using a library consisting of over 3000 biochemicals, we performed global metabolomic profiling in patient-derived GBM (n=80) and low-grade glioma (LGG; n=28). Alterations in fatty acid β-oxidation (FAO) emerged as a key metabolic node differentiating GBM from LGG, as demonstrated by an accumulation of acyl carnitines. Metabolic heterogeneity was observed within GBM that could further define tumors as FAO ‘high' and ‘low'. To begin to understand the molecular underpinnings of this metabolic heterogeneity, gene expression profiling on matched tumor samples was performed. We determined that established molecular subtypes of GBM correspond with FAO phenotypes, with FAO ‘high' and ‘low' tumors enriched with mesenchymal (MES) and proneural (PN) GBM subtypes, respectively. These findings were metabolomically and functionally recapitulated in molecular subtype-specific preclinical models, with an accumulation of acyl carnitines and enhanced FAO, contributing to nearly 60% of baseline cellular respiration, in MES glioma tumor initiating cells when compared to PN cells. Analysis of gene expression profiles from these lines uncovered an orchestrated transcriptional program designed to promote fatty acid uptake and activation. Consistent with gene expression findings, BODIPY labeling and fluorescent microscopy uncovered the unique capacity of MES cells to uptake fatty acids from the media, which was perturbed following FATP inhibition. Chemical and molecular inhibition of mediators of FAO, including fatty acid uptake, acylation, and CPT-1 demonstrated selective inhibition of proliferation in MES cells and inhibition of FAO using etomoxir demonstrated anti-tumor activity in vivo in an orthotopic model. Studies designed to determine the biologic consequence of enhanced FAO in GBM were not able to attribute this metabolic node to ATP synthesis. Systemic evaluation of the intermediary metabolism of FAO identified accumulation of the endogenous HDAC inhibitor 3HB and histone acetylation as consequence to enhanced FAO in GBM, which was also elevated in patient samples. The addition of 3HB rescued MES cells from the anti-proliferative effects of FAO inhibition and gene expression profiling identified FAO-mediated transcriptional programs contributing to the aggressive phenotype of MES in GBM. Collectively, our findings suggest that FAO represents a metabolic phenotype in GBM driven by enhanced fatty acid uptake and acylation, providing insight into both mechanisms driving the aggressive phenotype of this tumor and novel therapeutic targets. Citation Format: Shiva Kant, Antony Prabhu, Pravin Kesarwani, Praveen Kumar, Stewart F. Graham, Prakash Chinnaiyan. Integrative metabolomic and genomic analysis identifies fatty acid oxidation as a metabolic node in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3474.