Metabolomic and Lipidomic Profiling of Gliomas-A New Direction in Personalized Therapies

Abstract

In addition to being the most common primary brain tumor, gliomas are also among the most difficult to diagnose and treat. At present, the "gold standard" in glioma treatment entails the surgical resection of the largest possible portion of the tumor, followed by temozolomide therapy and radiation. However, this approach does not always yield the desired results. Additionally, the ability to cross the blood-brain barrier remains a major challenge for new potential drugs. Thus, researchers continue to search for targeted therapies that can be individualized based on the specific characteristics of each case. Metabolic and lipidomic research may represent two of the best ways to achieve this goal, as they enable detailed insights into the changes in the profile of small molecules in a biological system/specimen. This article reviews the new approaches to glioma therapy based on the analysis of alterations to biochemical pathways, and it provides an overview of the clinical results that may support personalized therapies in the future.

Keywords: gliomas; lipidomics; metabolomics; personalized medicine; pharmacotherapy.

Figure 1

Major metabolomic pathways involved in brain tumor metabolism. The highlighted boxes represent the potential metabolic pathways involved in the brain tumor: glycolytic intermediates, glutamine, lipids, and TCA cycle metabolites significantly alter in malignant brain tumors. The accumulation of oncometabolite 2-HG as a result of the IDH1/2 mutant also contributes to malignancy. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; dADP, deoxyadenosine diphosphate, dAMP, deoxyadenosine monophosphate; dATP, deoxyadenosine triphosphate; CoA, coenzyme A; GAR; glycinamide ribonucleotide; IDH, isocitrate dehydrogenase; UDP, uridine diphosphate. Reprinted with permission from [7].

Figure 2

Changes in metabolome and proteome under the influence of temozolomide. Reprinted from [40] with permission.

Figure 3

Reduction in metabolites associated with the TCA cycle after bevacizumab treatment. (a) Total metabolite levels (unlabeled and labeled) were quantified by LC–MS analysis. In addition to decreased glucose, glucose-6-phosphate and pryruvate levels, a reduction of metabolites associated with the TCA cycle was measured in the bevacizumab-treated tumors. These included pyruvate, cis-aconitate, α-ketoglutarate, succinate, fumarate and malate. Moreover, reduced levels of l-glutamine were observed following bevacizumab treatment. (b) Bevacizumab treatment led to reduced levels of glutathione and metabolites associated with glutathione synthesis, including l-cysteine, l-glutamate and l-glycine. Reprinted from [48] under the terms of the Creative Commons.

Figure 4

Illustration of fatty acid oxidation and synthesis in mitochondria. Fatty acids enter the mitochondria for β-oxidation to Acetyl CoA. Acetyl CoA enters the TCA cycle generating NADH. The NADH is then oxidized by the ETC, consuming oxygen or producing NADPH, as indicated. Endogenous fatty acids can be synthesized de novo from glucose or glutamine. Glucose is converted to pyruvate via a series of catabolic reactions, and the resultant pyruvate is either converted to lactate or enters the mitochondria to be converted to Acetyl CoA. Acetyl CoA enters the TCA cycle and exits as citrate, which is then exported to cytosol for the synthesis of fatty acids. Glutamine enters the TCA cycle after conversion to α-ketoglutarate (α-KG) and exits as malate and citrate into the cytosol for fatty acid synthesis. ETO: etomoxir, a CPT-1a inhibitor. Reprinted with permission from [75].

Figure 5

The metabolomic connection between the TCA cycle and TOP-2 inhibitor activity. When TCA cycle flux is low (green) topo II strand passage activity is not stimulated. General catalytic inhibitors (e.g., ICRF-187) that decrease topo II activity are more effective in this state, as compared with a high TCA state (orange). By contrast, topo II poisons (e.g., etoposide) are more toxic in the high TCA state because elevated topo II activity leads to increased formation of DNA cleavage complexes. Reprinted with permission from [79].