Arginine deprivation therapy for malignant melanoma

Abstract

Despite recent development of promising immunotherapeutic and targeted drugs, prognosis in patients with advanced melanoma remains poor, and a cure for this disease remains elusive in most patients. The success of melanoma therapy depends on a better understanding of the biology of melanoma and development of drugs that effectively target the relevant genes or proteins essential for tumor cell survival. Melanoma cells frequently lack argininosuccinate synthetase, an essential enzyme for arginine synthesis, and as a result they become dependent on the availability of exogenous arginine. Accordingly, a therapeutic approach involving depletion of available arginine has been shown to be effective in preclinical studies. Early clinical studies have demonstrated sufficient antitumor activity to give rise to cautious optimism. In this article, the rationale for arginine deprivation therapy is discussed. Additionally, various strategies for depleting arginine are discussed and the preclinical and clinical investigations of arginine deprivation therapy in melanoma are reviewed.

Pathways and therapeutic targets in melanoma

“…Arginine degradation using arginine deiminase (ADI) leads to growth inhibition and eventually cell death, while normal cells that express ASS can survive (reviewed by Yoon[316]). Pegylated ADI (ADI-PEG20) has shown antitumor activity in melanoma [317].…”

“…Another arginine- degrading enzyme, arginase, in a recombinant-pegylated and cobalt-substituted form, Co-ArgI-PEG, is being developed for clinical trials. It is already clear that treatment with ADI-PEG20 induces resistance in patients by at least two identified mechanisms: induction of protective autophagy and re-expression of ASS and activation of the MAPK pathway (reviewed by Yoon et al [316]). If arginine-deprivation therapy with arginine-degrading enzymes is to become a valid therapeutic option, concurrent therapies targeting autophagy or the MAPK pathway should be considered.…”

Arginine deprivation affects glioblastoma cell adhesion, invasiveness and actin cytoskeleton organization by impairment of β-actin arginylation

“…Although arginine deprivation-based enzymotherapy is at the developmental stage, it clearly bears a potential as an efficient, selective and relatively non-toxic approach against highly malignant ASS-negative tumors, e.g. bladder (Allen et al 2014 ), melanoma (Yoon et al 2013 ), pancreatic (Bowles et al 2008 ), prostate (Kim et al 2009 ), renal (Yoon et al 2007 ) carcinomas and glioblastomas (Syed et al 2013 ). For further optimization and development of rational combinational approaches, molecular signaling mechanisms governing tumor cell response to arginine deprivation have to be elucidated.…”

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

“…ADI-PEG20 is currently undergoing clinical investigation as a randomized double-blind phase III trial in patients with advanced HCC (NCT 01287585), phase II studies in patients with ASS-negative metastatic melanoma (NCT 01279967) and phase II studies in patients with relapsed small-cell lung cancer (NCT 01266018) 50 (Table 2). Outcomes of the previous clinical studies were also encouraging, achieving response rates of 25 and 47% in melanoma and HCC, respectively (Table 2).…”

“…Other promising targets include malignant pleural mesothelioma, renal cell carcinoma, prostate cancer, T-ALL and osteosarcoma. 50 However, molecular mechanisms underlying tumor sensitivity toward ADI treatment, by downregulation of ASS expression in tumor cells, are still elusive. Promoter hypermethylation-dependent silencing of ASS gene is an endorsed mechanism of ASS gene repression.…”