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

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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Figure 1: V-9302 is an inhibitor of glutamine transport.
Figure 2: In silico modeling of V-9302 interactions with hASCT2.
Figure 3: In vitro efficacy of V-9302.
Figure 4: Molecular determinants of ASCT2 antagonism in vitro.
Figure 5: Evaluation of V-9302 in vivo.
Figure 6: Summary of cancer cell programs modulated by V-9302.

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Acknowledgements

The authors acknowledge M. Tantawy for assistance with PET imaging, F. Revetta for histology expertise, and A. Rosenberg and A. Cohen for helpful discussions and editorial assistance. The authors wish to acknowledge research support from the Vanderbilt Ingram Cancer Center Support Grant (National Institutes of Health (NIH) National Cancer Institute (NCI) P30CA068485, H.C.M.), which supports the Vanderbilt-Ingram Cancer Center (VICC) Chemical Synthesis Core, Vanderbilt University Medical Center (VUMC) Radiochemistry Core, and Center for Small Animal Imaging; the Kleberg Foundation (H.C.M.); a Vanderbilt Trans-Institutional Program (TIPS) Award to the Vanderbilt Center for Molecular Probes (H.C.M.); the Vanderbilt Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer (NIH NCI P50CA095103, R.J.C. and H.C.M.); an Outstanding Investigator Award from the NCI (R35CA197570, R.J.C.); and the Vanderbilt Digestive Disease Research Center (NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) P30DK058404, H.C.M.).

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M.L.S. performed or designed most of the experiments with assistance from A.F., L.G., P.Z., and J.L. S.T.S. and J.A.S. performed computational modeling. J.K. and R.J.C. performed organoid studies. J.B. enrolled individuals who provided tissues for organoids and PDXs. J.T.S. and M.C.S. performed optical redox ratio measurements. M.O.J. and J.C.R. performed T cell experiments. M.K.W. interpreted pathology samples. M.L.N. oversaw radiopharmaceutical production and provided technical assistance. H.C.M. designed and supervised the study. M.L.S., M.L.N., and H.C.M. wrote the manuscript. All authors edited and approved the manuscript.

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Correspondence to H Charles Manning.

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The authors declare no competing financial interests.

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Schulte, M., Fu, A., Zhao, P. et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 24, 194–202 (2018). https://doi.org/10.1038/nm.4464

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