Amino acid metabolism in hematologic malignancies and the era of targeted therapy

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Abstract

The authors review the latest knowledge of amino acid metabolism in hematologic malignancies and the clinical relevance and potential of amino acid therapeutic targeting.

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Most cited references 72

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Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells and the most common malignant myeloid disorder in adults. The median age at presentation for patients with AML is 70 years. In the past few years, research in molecular biology has been instrumental in deciphering the pathogenesis of the disease. Genetic defects are thought to be the most important factors in determining the response to chemotherapy and outcome. Whereas significant progress has been made in the treatment of younger adults, the prospects for elderly patients have remained dismal, with median survival times of only a few months. This difference is related to comorbidities associated with ageing and to disease biology. Current efforts in clinical research focus on the assessment of targeted therapies. Such new approaches will probably lead to an increase in the cure rate.

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Hypoxia and metabolic adaptation of cancer cells

K L Eales, K E R Hollinshead, D A Tennant (2016)

Low oxygen tension (hypoxia) is a pervasive physiological and pathophysiological stimulus that metazoan organisms have contended with since they evolved from their single-celled ancestors. The effect of hypoxia on a tissue can be either positive or negative, depending on the severity, duration and context. Over the long-term, hypoxia is not usually consistent with normal function and so multicellular organisms have had to evolve both systemic and cellular responses to hypoxia. Our reliance on oxygen for efficient adenosine triphosphate (ATP) generation has meant that the cellular metabolic network is particularly sensitive to alterations in oxygen tension. Metabolic changes in response to hypoxia are elicited through both direct mechanisms, such as the reduction in ATP generation by oxidative phosphorylation or inhibition of fatty-acid desaturation, and indirect mechanisms including changes in isozyme expression through hypoxia-responsive transcription factor activity. Significant regions of cancers often grow in hypoxic conditions owing to the lack of a functional vasculature. As hypoxic tumour areas contain some of the most malignant cells, it is important that we understand the role metabolism has in keeping these cells alive. This review will outline our current understanding of many of the hypoxia-induced changes in cancer cell metabolism, how they are affected by other genetic defects often present in cancers, and how these metabolic alterations support the malignant hypoxic phenotype.

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Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target.

Luika A. Timmerman, Thomas Holton, Mariia Yuneva … (2013)

A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development. Copyright © 2013 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Title: Blood

Publisher: American Society of Hematology

ISSN (Print): 0006-4971

ISSN (Electronic): 1528-0020

Publication date Created: September 26 2019

Publication date Created: August 15 2019

Publication date (Print): September 26 2019

Publication date (Electronic): August 15 2019

Volume: 134

Issue: 13

Pages: 1014-1023

Affiliations

[1 ]Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;

[2 ]Department of Next Generation Hematology Laboratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; and

[3 ]Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX

Article

DOI: 10.1182/blood.2019001034

PMC ID: 6764269

PubMed ID: 31416801

SO-VID: 87dec23d-78b8-4a45-aa37-318f61daf2b0

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Amino acid metabolism in hematologic malignancies and the era of targeted therapy

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Cancer Metabolism

Most cited references 72

Acute myeloid leukaemia.

Hypoxia and metabolic adaptation of cancer cells

Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target.

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Cited by 75

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