2. Academic Validation
  3. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models

Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models

  • Nat Med. 2018 Feb;24(2):194-202. doi: 10.1038/nm.4464.
Michael L Schulte 1 2 3,  Allie Fu 1,  Ping Zhao 1,  Jun Li 1,  Ling Geng 1,  Shannon T Smith 1,  Jumpei Kondo 4,  Robert J Coffey 4 5 6,  Marc O Johnson 7,  Jeffrey C Rathmell 7,  Joe T Sharick 8,  Melissa C Skala 8,  Jarrod A Smith 9 10,  Jordan Berlin 5,  M Kay Washington 5 7,  Michael L Nickels 1 2 3,  H Charles Manning 1 2 3 5 8 11 12
Affiliations

Affiliations

  • 1 Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 2 Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 3 Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 4 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 5 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 6 Veterans Health Administration, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
  • 7 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 8 Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
  • 9 Vanderbilt Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.
  • 10 Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA.
  • 11 Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 12 Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
PMID: 29334372 DOI: 10.1038/nm.4464
Abstract

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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