Theranostics 2018; 8(8):2107-2116. doi:10.7150/thno.22083

Research Paper

Amino Acid Uptake Measured by [18F]AFETP Increases in Response to Arginine Starvation in ASS1-Deficient Sarcomas

Bethany Cheree Prudner1*, Fangdi Sun1,2*, Jeffrey Charles Kremer1, Jinbin Xu3, Chaofeng Huang3, Kiran Kumar Solingapuram Sai3, Zachary Morgan3, Hayden Leeds3, Jonathan McConathy3,4,5✉, Brian Andrew Van Tine1,4✉

1. Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
2. Harvard Medical School, Cambridge, MA, 02115, USA
3. Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
4. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA
5. Department of Radiology, University of Alabama at Birmingham, AL, 35249, USA
*There authors contributed equally to this work

Abstract

Rational: In a subset of cancers, arginine auxotrophy occurs due to the loss of expression of argininosuccinate synthetase 1 (ASS1). This loss of ASS1 expression makes cancers sensitive to arginine starvation that is induced by PEGylated arginine deiminase (ADI-PEG20). Although ADI-PEG20 treatment is effective, it does have important limitations. Arginine starvation is only beneficial in patients with cancers that are ASS1-deficient. Also, these tumors may metabolically reprogram to express ASS1, transforming them from an auxotrophic phenotype to a prototrophic phenotype and thus rendering ADI-PEG20 ineffective. Due to these limitations of ADI-PEG20 treatment and the potential for developing resistance, non-invasive tools to monitor sensitivity to arginine starvation are needed.

Methods: Within this study, we assess the utility of a novel positron emission tomography (PET) tracer to determine sarcomas reliant on extracellular arginine for survival by measuring changes in amino acid transport in arginine auxotrophic sarcoma cells treated with ADI-PEG20. The uptake of the 18F-labeled histidine analogue, (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (AFETP), was assessed in vitro and in vivo using human-derived sarcoma cell lines. In addition, we examined the expression and localization of cationic amino acid transporters in response to arginine starvation with ADI-PEG20.

Results: In vitro studies revealed that in response to ADI-PEG20 treatment, arginine auxotrophs increase the uptake of L-[3H]arginine and [18F]AFETP due to an increase in the expression and localization to the plasma membrane of the cationic amino acid transporter CAT-1. Furthermore, in vivo PET imaging studies in mice with arginine-dependent osteosarcoma xenografts showed increased [18F]AFETP uptake in tumors 4 days after ADI-PEG20 treatment compared to baseline.

Conclusion: CAT-1 transporters localizes to the plasma membrane as a result of arginine starvation with ADI-PEG20 in ASS1-deficient tumor cells and provides a mechanism for using cationic amino acid transport substrates such as [18F]AFETP for identifying tumors susceptible to ADI-PEG20 treatment though non-invasive PET imaging techniques. These findings indicate that [18F]AFETP-PET may be suitable for the early detection of tumor response to arginine depletion due to ADI-PEG20 treatment.

Keywords: Arginine, Arginine Deiminase, ADI-PEG20, AFETP, CAT1

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How to cite this article:
Prudner BC, Sun F, Kremer JC, Xu J, Huang C, Sai KKS, Morgan Z, Leeds H, McConathy J, Van Tine BA. Amino Acid Uptake Measured by [18F]AFETP Increases in Response to Arginine Starvation in ASS1-Deficient Sarcomas. Theranostics 2018; 8(8):2107-2116. doi:10.7150/thno.22083. Available from http://www.thno.org/v08p2107.htm