Journal
NATURE MEDICINE
Volume 24, Issue 2, Pages 194-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4464
Keywords
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Funding
- Vanderbilt Ingram Cancer Center (National Institutes of Health (NIH) National Cancer Institute (NCI)) [P30CA068485]
- Center for Small Animal Imaging
- Kleberg Foundation
- Vanderbilt Trans-Institutional Program (TIPS) Award
- Vanderbilt Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer [NIH NCI P50CA095103]
- NCI [R35CA197570]
- Vanderbilt Digestive Disease Research Center (NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)) [P30DK058404]
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The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.
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