Cancer Res Treat.  2013 Dec;45(4):251-262.

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

• Phillips M
• Sheaff MT
• Szlosarek

Abstract

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.

Keyword

Neoplasms; Arginine; Argininosuccinate synthetase; Argininosuccinate lyase; ADI-PEG20; Arginase; Drug combinations

MeSH Terms

Arginase
Arginine
Argininosuccinate Lyase
Argininosuccinate Synthase
Biomarkers
Carcinoma, Hepatocellular
Drug Combinations
Epigenomics
Glioblastoma
Humans
Kidney Neoplasms
Lymphoma
Melanoma
Sarcoma
Urea
Urologic Neoplasms
Arginase
Arginine
Argininosuccinate Lyase
Argininosuccinate Synthase
Drug Combinations
Urea

Figure

• 

  Fig. 1 Heterogeneity of argininosuccinate synthetase 1 (ASS1) expression in lung adenocarcinoma. Immunohistochemical staining (BD ASS1 antibody 1:500, BioGenex Super Sensitive Detection System) of a non-small cell lung cancer composed of a mixed population of ASS1 positive and negative tumor cells (×400).

• 

  Fig. 2 Multiagent chemotherapy for arginine auxotrophic cancers. Applying the analogy of ten-pin bowling, a 'strike' is rarely seen in cancer therapy whereas a 'half-strike' is more likely with multiagent drug regimens; various drug combination studies are underway including the example shown here of the triplet, ADI-PEG20, cisplatin and pemetrexed. ASS1, argininosuccinate synthetase 1.

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