Current Status and Future Prospects of Clinically Exploiting Cancer-specific Metabolism-Why Is Tumor Metabolism Not More Extensively Translated into Clinical Targets and Biomarkers?

Abstract

Tumor cells exhibit a specialized metabolism supporting their superior ability for rapid proliferation, migration, and apoptotic evasion. It is reasonable to assume that the specific metabolic needs of the tumor cells can offer an array of therapeutic windows as pharmacological disturbance may derail the biochemical mechanisms necessary for maintaining the tumor characteristics, while being less important for normally proliferating cells. In addition, the specialized metabolism may leave a unique metabolic signature which could be used clinically for diagnostic or prognostic purposes. Quantitative global metabolic profiling (metabolomics) has evolved over the last two decades. However, despite the technology's present ability to measure 1000s of endogenous metabolites in various clinical or biological specimens, there are essentially no examples of metabolomics investigations being translated into actual utility in the cancer clinic. This review investigates the current efforts of using metabolomics as a tool for translation of tumor metabolism into the clinic and further seeks to outline paths for increasing the momentum of using tumor metabolism as a biomarker and drug target opportunity.

Keywords: biomarker; cancer; drug discovery; metabolic homeostasis; metabolism; metabolomics; translational medicine; tumor.

Figure 1

(A) Maintaining ATP is performed with extreme precision. This causes metabolic ripple effects throughout the metabolism. Glycolysis and tricarboxylic acid (TCA) cycle are central nodes in this. (B) Metabolic homeostasis can be maintained primarily by the mechanics of regulation of fluxes (left) and alternative pathways or shunts for diversion of metabolic flow. (C) Conversion of glutamine to glutamate is most often associated with the enzyme glutaminase (GLS). There are, however, at least 11 other paths between these metabolites with experimental evidence. (1) glutamate dehydrogenase 1 (GLUD1), (2) phosphoserine aminotransferase (PSAT1), (3) tyrosine aminotransferase (TAT), (4) aspartate aminotransferase 1 (GOT1), (5) alanine aminotransferase 1 (GPT), (6) 4-aminobutyrate aminotransferase, mitochondrial (ABAT), (7) kynurenine/alpha-aminoadipate aminotransferase (AADAT), and (8) ornithine aminotransferase (OAT).

Figure 2

Schematic illustration of how drugs or drug targets are involved in cancer metabolic pathways.