TY - JOUR
T1 - Amino acid uptake measured by [ 18 F]AFETP increases in response to arginine starvation in ASS1-deficient sarcomas
AU - Prudner, Bethany Cheree
AU - Sun, Fangdi
AU - Kremer, Jeffrey Charles
AU - Xu, Jinbin
AU - Huang, Chaofeng
AU - Sai, Kiran Kumar Solingapuram
AU - Morgan, Zachary
AU - Leeds, Hayden
AU - McConathy, Jonathan
AU - Van Tine, Brian Andrew
N1 - Funding Information:
The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant #P30 CA91842. This research was funded by the National Cancer Institute (K08CA154790; P50CA94056).
Publisher Copyright:
© Ivyspring International Publisher.
PY - 2018
Y1 - 2018
N2 - 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 18 F-labeled histidine analogue, (S)-2-amino-3-[1-(2-[ 18 F]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-[ 3 H]arginine and [ 18 F]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 [ 18 F]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 [ 18 F]AFETP for identifying tumors susceptible to ADI-PEG20 treatment though non-invasive PET imaging techniques. These findings indicate that [ 18 F]AFETP-PET may be suitable for the early detection of tumor response to arginine depletion due to ADI-PEG20 treatment.
AB - 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 18 F-labeled histidine analogue, (S)-2-amino-3-[1-(2-[ 18 F]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-[ 3 H]arginine and [ 18 F]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 [ 18 F]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 [ 18 F]AFETP for identifying tumors susceptible to ADI-PEG20 treatment though non-invasive PET imaging techniques. These findings indicate that [ 18 F]AFETP-PET may be suitable for the early detection of tumor response to arginine depletion due to ADI-PEG20 treatment.
KW - ADI-PEG20
KW - AFETP
KW - Arginine
KW - Arginine Deiminase
KW - CAT1
UR - http://www.scopus.com/inward/record.url?scp=85043485538&partnerID=8YFLogxK
U2 - 10.7150/thno.22083
DO - 10.7150/thno.22083
M3 - Article
C2 - 29721066
AN - SCOPUS:85043485538
SN - 1838-7640
VL - 8
SP - 2107
EP - 2116
JO - Theranostics
JF - Theranostics
IS - 8
ER -