Arginine auxotrophic gene signature in paediatric sarcomas and brain tumours provides a viable target for arginine depletion therapies

Vardon, Ashley; Dandapani, Madhumita; Cheng, Daryl R; Cheng, Paul; Santo, Carmela De; Mussai, Francis

doi:10.18632/oncotarget.18843

Cited by 18 publications

(20 citation statements)

References 63 publications

(48 reference statements)

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“…A reduced transcription level of one of those genes was seen in particular in cells with normal ASS1/ASL expression [31]. Supporting these findings, a recent report described significant downregulation of OTC in pediatric sarcomas and brain tumors with normal ASS1 expression [32].…”

Section: Arginine Auxotrophy In Human Malignanciessupporting

confidence: 52%

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches.

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Section: Arginine Auxotrophy In Human Malignanciessupporting

confidence: 52%

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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“…[4][5][6][7] Peripheral blood arginine concentrations are lower than healthy controls in AML, neuroblastoma, and pediatric cancer patients at diagnosis (Figure 1A-C) and Arginase I is expressed within the tumor microenvironments of adult tumor subtypes (supplemental Figure 1A-B, available on the Blood Web site). 8 T cells are acutely sensitive to extracellular concentrations of arginine because they have low/ absent expression of the arginine resynthesis pathway enzymes ASS and OTC (supplemental Figures 1C and 2A). [9][10][11][12] We hypothesized that insertion of ASS and/or OTC enzymes would allow CAR-T cells to refuel themselves, in a low arginine microenvironment.…”

Section: Resultsmentioning

confidence: 99%

Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity

Fultang

Booth

Yogev

et al. 2020

Blood

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102

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Haematological and solid cancers catabolise the semi-essential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against haematological and solid malignancies. T cells are susceptible to the low arginine microenvironment due to the low expression of the arginine re-synthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate T cells can be re-engineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukaemia or solid tumour burden, providing the first metabolic modification to enhance CAR-T cell therapies.

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“…In hepatocellular carcinoma, reduced expression of CPS1 is linked to hypermethylation of the promoter and is related to reduced survival and lymphatic invasion [ 66 ]. A recent study reported decreased OTC expression in HCC patients’ samples; OTC is one of the characteristic arginine metabolism genes in pediatric sarcomas, brain tumors, and acute lymphoblastic leukemia [ 67 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines

Zhang

Tang

et al. 2021

Molecules

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The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation.

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Arginine auxotrophic gene signature in paediatric sarcomas and brain tumours provides a viable target for arginine depletion therapies

Cited by 18 publications

References 63 publications

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity

Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines

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