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.

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo

“…3,4 Cells may either import arginine or synthesize it from citrulline through the enzymes argininosuccinate synthetase-1 (ASS1) and argininosuccinate lyase (ASL) ( Figure 1A). [4][5][6] ASS1 is not expressed by many malignant cells, and this appears to confer a proliferative advantage to the cells. [7][8][9] Overexpression and silencing of ASS1 in cancer cell lines reduce and increase proliferation, respectively.…”

Proliferation of sphere-forming hepatocellular carcinoma cells is suppressed in a medium without glucose and arginine, but with galactose and ornithine

“…The results suggest that the deprivation of glucose and arginine may be an effective approach for the treatment of HCC. Furthermore, the efficacy of arginase, which metabolizes arginine, has been previously demonstrated in HCC (33). The combination of 2DG and arginase must be investigated in further studies as a potential strategy for the treatment of HCC.…”

Drug target identification at the crossroad of neuronal apoptosis and survival

“…Some studies have focused on the inactivation of these enzymes in a range of malignancies. Drugs like pegylated arginine deiminase/ADI-PEG20 (Polaris Group) (Als inhibitor) [47], xanthohumol (Dio3 inhibitor) [48], 1,10-phenanthroline (Gpld1 inhibitor) [49], compounds 54, 66, and 67 (inhibitors of Hsd3b5) [50], and alpha-difluoromethylornithine (Odc1 inhibitor) [51] have already been reported to act as sensitizing anticancer agents. Deregulation of Asah1, an acid ceramidase, and Nmnat2, a nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme, has been involved in a variety of neurodiseases and/or cancers [52,53].…”