Cited by 1,169Cancer, Hypoxia, and MetabolismCancer Immunotherapy and BiomarkersImmune cells in cancer

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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

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Leone, Robert D., Zhao, Liang, Englert, Judson M., Sun, Im-Meng, Oh, Min-Hee, Sun, Im-Hong, Arwood, Matthew L., Bettencourt, Ian A., Patel, Chirag H., Wen, Jiayu, Tam, Ada, Blosser, Richard L., Prchalova, Eva, Alt, Jesse, Rais, Rana, Slusher, Barbara S., Powell, Jonathan D.·2019·Science

DOI 10.1126/science.aav2588PMC PMC7023461

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Abstract

A fresh look at glutamine targeting: Glutamine is essential for tumor growth and has long been an attractive therapeutic target for cancer researchers. Some attempts at blocking glutamine metabolism in cancer patients resulted in toxicity, prompting Leone et al. to develop an innovative approach to reduce general side effects. They designed a prodrug form (JHU083) of the glutamine antagonist 6-diazo-5-oxo- l -norleucine (DON), which is administered in an inert state but then preferentially activated by enzymes enriched in the tumor microenvironment. JHU083 simultaneously shut down glycolysis and oxidative phosphorylation in mouse cancer cells while enhancing T cell oxidative phosphorylation and anticancer immune responses. Science , this issue p. 1013

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Influential
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Authors: Leone, R. D., Zhao, L., Englert, J. M., Sun, I.-M., Oh, M.-H., Sun, I.-H., Arwood, M. L., Bettencourt, I. A., Patel, C. H., Wen, J., Tam, A., Blosser, R. L., Prchalova, E., Alt, J., Rais, R., Slusher, B. S., & Powell, J. D.
Affiliations: Johns Hopkins University (US)
Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Corresponding author: Powell, Jonathan D.
ORCID: Leone, Robert D.
Zhao, Liang
Englert, Judson M.
Sun, Im-Meng
Oh, Min-Hee
Sun, Im-Hong
Arwood, Matthew L.
Bettencourt, Ian A.
Patel, Chirag H.
Wen, Jiayu
Tam, Ada
Blosser, Richard L.
Alt, Jesse
Rais, Rana
Slusher, Barbara S.
Powell, Jonathan D.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2019-11-22
Volume: 366
Issue: 6468
Pages: 1013-1021
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.aav2588
PMC: PMC7023461
OpenAlex: W2985764787
Cited by: 1,169
References: 57
Citations by year: 2026: 143 · 2025: 196 · 2024: 195 · 2023: 181 · 2022: 197 · 2021: 160 · 2020: 92 · 2019: 4
FWCI: 35.99
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIH Office of the Director (R01CA226765, R01CA229451)
The Bloomberg∼Kimmel Institute for Cancer Immunotherapy.
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords: glutamine antagonist, tumor immune evasion, tumor microenvironment, cancer metabolism, oxidative metabolism, glycolysis, tumor hypoxia, tumor acidosis, effector T cells, antitumor immunity, metabolic checkpoint, cancer immunotherapy
MeSH terms: Animals, Azo Compounds, Caproates, Citric Acid Cycle, Energy Metabolism, Female, Glucose, Glutamine, Immunologic Memory, Lymphocyte Activation, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Tumor Escape, Tumor Microenvironment

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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

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