Targeting cancer metabolism: a therapeutic window opens

Key Points

  • Proliferating cells exhibit different metabolic requirements to non-proliferating cells, and the changes in cell metabolism that are associated with cancer support the increased biosynthesis of these proliferating cells to enable the characteristic dysregulated cell proliferation that is observed in cancer.

  • All cancer cells have to solve the same metabolic problem of directing available nutrients into biosynthetic pathways while maintaining adequate levels of ATP to maintain homeostasis, which suggests that targeting metabolic pathways is a therapeutic approach that could be applied to many cancers.

  • Normal proliferating cells have similar metabolic requirements to cancer cells, which raises questions about whether a sufficient therapeutic window exists to develop anticancer drugs that target cell metabolism.

  • Tumour metabolism is heterogeneous, with both genetics and the tumour microenvironment influencing metabolism; this can create potential therapeutic opportunities to limit toxicity resulting from the effects of anticancer therapies on normal proliferating cells.

  • Some currently successful cancer therapies have been shown to target metabolism, which demonstrates that it is possible to safely target tumour metabolism in patients.

  • Preclinical studies have indicated specific metabolic enzymes as targets for cancer therapy, and ongoing efforts to understand how cell metabolism is regulated in tumour cells will define the most effective way of translating these ideas into better patient care.

Abstract

Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.

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Figure 1: Cancer cell metabolism.
Figure 2: Existing chemotherapies targeting specific metabolic enzymes.
Figure 3: Targeting metabolic enzymes as a strategy to block biosynthesis or induce energy stress.

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Acknowledgements

Thanks to D. Schenkein, L. Whitesell, B. Wolpin, K. Courtney, P. Ward and members of the Vander Heiden Laboratory for helpful discussions and comments on the manuscript. Special thanks to B. Bevis and S. Y. Lunt for advice and help with the generation of the figures. The author acknowledges support from the Burrough's Wellcome Fund, the Smith Family Foundation, the Starr Cancer Consortium, the Damon Runyon Cancer Research Foundation and the US National Institutes of Health.

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Matthew Vander Heiden discloses an advisory relationship with Agios Pharmaceuticals.

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Glossary

Therapeutic window

A term describing the ability of a drug to treat a disease effectively without causing unacceptable toxicity.

Aerobic glycolysis

The metabolism of glucose to lactate in the presence of oxygen. This is sometimes also referred to as the 'Warburg effect'.

18F-deoxyglucose positron emission tomography

(FDG–PET). A medical imaging test that is used in the clinic to visualize tissues with increased glucose uptake, including tumours.

Tumour microenvironment

The local conditions experienced by cells in a tumour, including the levels of nutrients, oxygen and signalling molecules such as growth factors and cytokines.

Metabolic enzymes

Proteins that catalyse the interconversion of two metabolites.

Cancer cell metabolism

The enzymes and pathways used by cancer cells to transform nutrients into the chemical precursors that make up a cell, and to generate ATP and reducing equivalents that support cellular processes.

Auxotroph

A term describing the inability of a cell (or organism) to synthesize a chemical compound that is required for growth or survival.

Lactic acidosis

A condition of low blood pH (metabolic acidosis) that is caused by the accumulation of lactate.

Metabolite profiling

The measurement of multiple metabolite levels in cells or in body fluid. This is sometimes also referred to as metabolomics. Metabolites are usually detected using nuclear magnetic resonance spectroscopy or mass spectrometry.

Mitochondrial membrane potential

The electrochemical proton gradient across the inner mitochondrial membrane that is generated by the mitochondrial electron transport chain. This gradient is used to synthesize ATP and transport molecules across the inner mitochondrial membrane.

Central carbon metabolism

The core metabolic pathways used by cells to generate ATP, reducing equivalents and the main precursors for amino acid, nucleic acid and lipid biosynthesis.

Bioenergetics

A term referring to how energy flows through living systems.

Lymphopaenia

A clinical term referring to an abnormally low number of lymphocytes in the blood.

Metabolic flux

The rate by which molecules flow through a metabolic pathway. Flux through metabolic pathways is regulated by cells to support cellular processes, and is the composite outcome of: enzyme levels; genetic, allosteric and post-translational regulation of enzymes; and concentrations of metabolites.

Anapleurosis

A term describing the requirement of metabolites to replenish a metabolic cycle when the metabolic intermediates that are involved in the cycle are depleted for use in reactions outside the cycle. The classic example of this process is replenishing those intermediates that are depleted from the tricarboxylic acid cycle for biosynthesis, in order to allow the cycle to continue functioning.

Redox state

A term capturing the reduction–oxidation state of a system. For cells this refers to the propensity of redox couples — such as reduced and oxidized glutathione or NADH and NAD+ — to be in one state or the other.

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Vander Heiden, M. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10, 671–684 (2011). https://doi.org/10.1038/nrd3504

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