Renewed interest in the use of therapeutic enzymes combined with an improved knowledge of cancer cell metabolism, has led to the translation of several arginine depletion strategies into early phase clinical trials. Arginine auxotrophic tumors are reliant on extracellular arginine, due to the downregulation of arginosuccinate synthetase or ornithine transcarbamylase-key enzymes for intracellular arginine recycling. Engineered arginine catabolic enzymes such as recombinant human arginase (rhArg1-PEG) and arginine deiminase (ADI-PEG) have demonstrated cytotoxicity against arginine auxotrophic tumors. In this review, we discuss the molecular events triggered by extracellular arginine depletion that contribute to tumor cell death.
Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated-recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating-monocytes to a M1-macrophage phenotype, which released IL-1β and TNF-α in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL-1β and TNF-α established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signalling in neuroblastoma and neural crest-derived cells. Proteomic analysis revealed that enrichment of IL-1β and TNF-α in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited.
Arginine is a semi‐essential amino acid that plays a key role in cell survival and proliferation in normal and malignant cells. BCT‐100, a pegylated (PEG) recombinant human arginase, can deplete arginine and starve malignant cells of the amino acid. Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood, yet for patients with high risk or relapsed disease prognosis remains poor. We show that BCT‐100 is cytotoxic to ALL blasts from patients in vitro by necrosis, and is synergistic in combination with dexamethasone. Against ALL xenografts, BCT‐100 leads to a reduction in ALL engraftment and a prolongation of survival. ALL blasts express the arginine transporter CAT‐1, yet the majority of blasts are arginine auxotrophic due to deficiency in either argininosuccinate synthase (ASS) or ornithine transcarbamylase (OTC). Although endogenous upregulation or retroviral transduced increases in ASS or OTC may promote ALL survival under moderately low arginine conditions, expression of these enzymes cannot prevent BCT‐100 cytotoxicity at arginine depleting doses. RNA‐sequencing of ALL blasts and supporting stromal cells treated with BCT‐100 identifies a number of candidate pathways which are altered in the presence of arginine depletion. Therefore, BCT‐100 provides a new clinically relevant therapeutic approach to target arginine metabolism in ALL.
Paediatric sarcomas and brain tumours, remain cancers of significant unmet need, with a poor prognosis for patients with high risk disease or those who relapse, and significant morbidities from treatment for those that survive using standard treatment approaches. Novel treatment strategies, based on the underlying tumour biology, are needed to improve outcomes. Arginine is a semi-essential amino acid that is imported from the extracellular microenvironment or recycled from intracellular precursors through the combined expression of the enzymes ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL) enzymes. The failure to express at least one of these recycling enzymes makes cells reliant on extracellular arginine – a state known as arginine auxotrophism. Here we show in large in silico patient cohorts that paediatric sarcomas and brain tumours express predominately the arginine transporter SLC7A1 and the arginine metabolising enzyme Arginase 2 (ARG2), but have low-absent expression of OTC. The arginine metabolic pathway correlated with the expression of genes associated with tumour pathogenesis, and overall survival in paediatric sarcomas. This gene signature of arginine auxotrophism indicates paediatric sarcomas and brain tumours are a viable target for therapeutic arginase drugs under current clinical trial development.
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