Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges

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.

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

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.