Evaluation of Arginine Deiminase Treatment in Melanoma Xenografts Using 18F-FLT PET

Stelter, Lars; Fuchs, Simon; Jungbluth, Achim A.; Ritter, Gerd; Longo, Valerie A.; Zanzonico, Pat; Raschzok, Nathanael; Sauer, Igor M.; Bomalaski, John S.; Larson, Steven M.

doi:10.1007/s11307-013-0655-6

Cited by 11 publications

(11 citation statements)

References 35 publications

(39 reference statements)

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“…This is in contrast to recent work with ADI-PEG20 in ASS1-negative melanoma xenografts in which there was no effect on TK1 expression and FLT-PET metabolic responses were not detected (41). These and previous results using 2 [ 18 F]fluoro-2-deoxy-D-glucose tracers may be explained in part by the differential regulation of ASS1 promoter with HIF-1a-mediated repression in melanoma compared with epigenetic silencing identified in several other arginine auxotrophic cancers (9,16,42).…”

Section: Discussioncontrasting

confidence: 99%

Prognostic and Therapeutic Impact of Argininosuccinate Synthetase 1 Control in Bladder Cancer as Monitored Longitudinally by PET Imaging

et al. 2014

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Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [ 18 F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response. Cancer Res; 74(3); 896-907. Ó2013 AACR.

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Section: Discussioncontrasting

confidence: 99%

Prognostic and Therapeutic Impact of Argininosuccinate Synthetase 1 Control in Bladder Cancer as Monitored Longitudinally by PET Imaging

et al. 2014

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“…Thus, we and others have explored FLT as an alternative imaging PET tracer and although this does not appear predictive in ASS1-negative melanoma, our studies confirmed robust suppression of FLT uptake following ADI-PEG20 treatment of ASS1-methylated tumors [20,106]. Moreover, the uptake of FLT correlated directly with thymidine-kinase 1 (TK1) protein levels consistent with the mode of action of ADI-PEG20 in modulating protein turnover.…”

Section: Imaging Arginine Depletion In Human Cancermentioning

confidence: 54%

“…One of the drawbacks in imaging some arginine auxotrophs such as melanoma, is the apparent increase in glucose uptake following ADI-PEG20 therapy secondary to PTEN loss and PI3K-induced glucose transporter type 1 (GLUT-1) expression [ 47 ]. Thus, we and others have explored FLT as an alternative imaging PET tracer and although this does not appear predictive in ASS1-negative melanoma, our studies confirmed robust suppression of FLT uptake following ADI-PEG20 treatment of ASS1-methylated tumors [ 20 , 106 ]. Moreover, the uptake of FLT correlated directly with thymidine-kinase 1 (TK1) protein levels consistent with the mode of action of ADI-PEG20 in modulating protein turnover.…”

Section: Imaging Arginine Depletion In Human Cancermentioning

confidence: 58%

Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges

2013

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Arginine deprivation is a novel antimetabolite strategy for the treatment of arginine-dependent cancers that exploits differential expression and regulation of key urea cycle enzymes. Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma (HCC), mesothelial and urological cancers, sarcomas, and lymphomas. Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group) and bioengineered forms of human arginase. ADI-PEG20 is furthest along the path of clinical development from combinatorial phase 1 to phase 3 trials and is described in more detail. The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response. Lastly, resistance pathways to arginine deprivation require further study to optimize arginine-targeted therapies in the oncology clinic.

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“…34 Importantly, the effects of combination chemotherapy are likely to be tumor cell type specific, as evidenced by the differential modulation of enzymes involved in nucleotide synthesis after treatment with ADI-PEG20 in mesothelioma compared with melanoma. 11 , 35 In the case of platinum agents, resistance has been observed in ovarian cancer and NSCLC cell lines displaying loss of ASS1, whereas ADI-PEG 20 has been shown to induce cisplatin sensitivity in the latter. 9 , 36 Further work will be needed to optimize antimetabolite combinations on the basis of careful biomarker analyses to identify the role of arginine deprivation in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1–Deficient Thoracic Cancers

Beddowes

Spicer

Chan

et al. 2017

JCO

100

118

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PurposePegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) –negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non–small-cell lung cancer (NSCLC).Patients and MethodsUsing a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM.ResultsNo dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM.ConclusionTarget engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.

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Evaluation of Arginine Deiminase Treatment in Melanoma Xenografts Using 18F-FLT PET

Cited by 11 publications

References 35 publications

Prognostic and Therapeutic Impact of Argininosuccinate Synthetase 1 Control in Bladder Cancer as Monitored Longitudinally by PET Imaging

Prognostic and Therapeutic Impact of Argininosuccinate Synthetase 1 Control in Bladder Cancer as Monitored Longitudinally by PET Imaging

Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1–Deficient Thoracic Cancers

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