Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment

Abstract

Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis-all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal.

Keywords: ADI-PEG 20; BCT-100; arginine auxotrophic cancer; arginine deprivation cancer therapy; biomarker; circulating arginine; rhArg1-PEG.

Figure 1

The diagram illustrates the metabolic pathways of arginine in human cells. Normally, free arginine can be obtained from extracellular sources through transporters to enter the cell, or it can be synthesized de novo from citrulline and aspartate in the urea cycle. Arginine can be further metabolized into nitric oxide (NO), urea, agmatine, and ornithine. Agmatine and ornithine serve as precursors for putrescine and downstream metabolites, polyamines. Ornithine can also be transported into the mitochondria for further processing to generate citrulline, which is then exported from the mitochondria and enters the urea cycle. Both NO and polyamines have been implicated in cancer initiation and progression and are considered key metabolites. Abbreviation: ASS1, argininosuccinate synthetase 1; ASL, argininosuccinate lyase; ADC, arginine decarboxylase; AGM, agmatinase; ODC, ornithine decarboxylase; ARG, arginase; NOS, nitric oxide synthase.

Figure 2

Concept of using arginine-depleting enzymes in arginine deprivation for cancer treatment. Cancer cells that lack the ASS1 enzyme and require external sources of arginine are susceptible to this therapy. Three categories of arginine-depleting enzymes, including arginine deiminase related (ADI-PEG 20, SpyADI, NEI-01), arginase related (rhArg1-PEG, HAI-PEG 20 or BCA), and arginine decarboxylase related (rhADC), can be used to block the external supply of arginine, leading to cancer cell death through autophagy or apoptosis. ADI, arginine deiminase; SpyADI, Streptococcus pyogenes ADI; Arg, arginase; HAI-PEG 20, human arginase 1 mutant-PEG 20; BCA, Bacillus Caldovelox arginase; ASS1, argininosuccinate synthetase 1.

Figure 3

The diagram highlights potential biomarkers that can aid in patient selection for arginine deprivation anticancer therapy. These biomarkers encompass lower levels of ASS1 and WWOX proteins in tissues (red arrow pointing down), in addition to increased expression of HIF-1 protein (red arrow pointing up). Furthermore, genetic variations, including mutations in the BAP1 and BRAF genes, as well as single nucleotide polymorphism (SNP) variations, specifically WWOX-rs13338697 and rs6025211, may also serve as biomarkers. Additionally, pre-treatment and post-treatment circulating arginine levels can be used to predict the therapeutic efficacy of this therapy for cancer treatment. Patients highlighted in gray may not respond to arginine deprivation therapy, while those in green may potentially have a positive response to this therapy. Abbreviation: ASS1, arginosuccinate synthetase 1; HIF-1, hypoxia-inducible factor-1, WWOX, WW-domain-containing oxidoreductase; BAP1, BRCA1 associated protein 1; BRAF, B-Raf proto-oncogene, serine/threonine kinase.