Metastatic
melanoma is a deadly form of
cancer with few therapeutic options and the cause of more than 9480 deaths annually in the USA alone. Novel treatment options for this disease are urgently needed. Here we test the efficacy of a novel
melanoma drug, the human recombinant Co-
arginase (
CoArgIPEG), against an aggressive A375
melanoma mouse model.
CoArgIPEG is a modification of the naturally occurring human
enzyme with improved stability, catalytic activity, and potentially lower immunogenicity compared with current
amino acid-depleting drugs. Marked
tumor growth reductions (mean P=0.0057) with apoptosis induction and proliferation inhibition are noted with
CoArgIPEG treatment, both in the presence and in the absence of supplemental
citrulline. Further, improved therapeutic efficacy has been noted against A375 xenografts relative to the naturally occurring human recombinant
arginase enzyme at lower doses of
CoArgIPEG. Unfortunately, after 1 month, half of the relapsing
tumors showed
argininosuccinate synthase induction, which correlated with Ser62-phosphorylated cMyc. Although
argininosuccinate synthase induction could not be induced in vitro, a drug targeting pathway previously demonstrated to be associated with Ser62 cMyc phosphorylation -
U0126 - in combination with
CoArgIPEG demonstrated an in-vitro synergistic response (combination indices 0.13±0.10 and 0.14±0.10 with or without
citrulline, respectively). Overall, favorable efficacy and potential synergy with other antimelanoma drugs support
CoArgIPEG as a potent, novel
cancer therapeutic.