Amino acid PET for monitoring response to ADI-PEG20 therapy in an ASS1 negative model of sarcoma

Objectives Many chemotherapy resistant cancers such as sarcomas are dependent on extracellular L-arginine (Arg) due to defects in the urea cycle from the lack of the enzyme argininosuccinate synthetase 1 (ASS1). This dependence can be exploited therapeutically using pegylated arginine deiminase (ADI-PEG20) to deplete extracullular Arg. This study assessed the potential of PET using the ¹⁸F-labeled histidine analogue, (S)-AFETP, for early identification of response to Arg depletion therapy in a mouse model of sarcoma. We hypothesized that ASS1 negative sarcomas would increase the rate of Arg transport in response to Arg depletion.

Methods In vitro uptake assays using L-³H-arginine and ¹⁸F-AFETP were performed in the human-derived sarcoma ASS1 negative SKLMS1 and the ASS1 positive MG63 cell lines incubated in control media and after 48 hours of incubation in media containing ADI-PEG20. The cellular uptake after 5 min of incubation was measured and normalized for protein concentration. Small animal PET studies were performed in three male nu/nu mice with subcutaneous SKLMS1 tumors. Dynamic 0-60 min data were acquired at baseline and on days 2 and 4 of ADI-PEG20 therapy. Volumes of interest were drawn manually over the tumors, and the average standardized uptake values (SUVs) were compared before and ADI-PEG20 therapy.

Results In response to Arg depletion, uptake of Arg and AFETP increased in ASS1 negative cells by approximately 33% and 300%, respectively, but not in ASS1 positive cells. AFETP-PET imaging demonstrated good tumor visualization with average tumor SUV increases of 50% and 30% on days 2 and 4 compared to baseline, respectively.

Conclusions AFETP-PET is a promising technique for monitoring the adaptive response of ASS1 negative tumors to ADI-PEG20 therapy. Studies are ongoing to further define the utility of AFETP-PET for this application and for ASS1 positive tumors.

Research Support Washington University BRIGHT Institute, Polaris Group, NCI K08CA154790