Novel mechanistic insights into arginine deiminase pharmacology suggest 18F-FDG is not suitable to evaluate clinical response in melanoma.
Because of deficiencies in l-arginine biosynthesis, some cancers are susceptible to therapeutic intervention with arginine deiminase (ADI), an enzyme responsible for consuming the dietary supply of l-arginine to deprive the disease of an essential nutrient. ADI is currently being evaluated in several clinical trials, and fully realizing the drug's potential will depend on invoking the appropriate metrics to judge clinical response. Without a clear biologic mandate, PET/CT with (18)F-FDG is currently used to monitor patients treated with ADI. However, it is unclear if it can be expected that (18)F-FDG responses will indicate (or predict) clinical benefit.


METHODS
(18)F-FDG responses to ADI therapy were studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was also studied, with a particular emphasis on biologic pathways known to regulate (18)F-FDG avidity.


RESULTS
Although proliferation of SK-MEL 28 was potently inhibited by ADI treatment in vitro and in vivo, no clear declines in (18)F-FDG uptake were observed. Further investigation showed that ADI treatment induces the posttranslational degradation of phosphatase and tensin homolog and the activation of the PI3K signaling pathway, an event known to enhance glycolysis and (18)F-FDG avidity. A more thorough mechanistic study showed that ADI triggered a complex mechanism of cell death, involving apoptosis via poly (ADP-ribose) polymerase cleavage-independent of caspase 3.


CONCLUSIONS
These findings suggest that some unexpected pharmacologic properties of ADI preclude using (18)F-FDG to evaluate clinical response in melanoma and, more generally, argue for further studies to explore the use of PET tracers that target apoptotic pathway activation or cell death.
Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. lars.stelter@charite.de
Lars
L
Stelter
Michael J
MJ
Evans
Achim A
AA
Jungbluth
Pat
P
Zanzonico
Gerd
G
Ritter
Thomas
T
Ku
Eric
E
Rosenfeld
John S
JS
Bomalaski
Lloyd
L
Old
Steven M
SM
Larson
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology* / Q000627:therapeutic use; D008545:Melanoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D049268:Positron-Emission Tomography; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D019788:Fluorodeoxyglucose F18; D006867:Hydrolases; C019723:arginine deiminase