October 2, 2023

This paper characterises the expression of arginine pathway enzymes in several paediatric CNS tumours, namely, high-grade glioma (pHGG), paediatric low-grade glioma (LGG), ependymoma (EPN), and medulloblastoma (MB)

This paper characterises the expression of arginine pathway enzymes in several paediatric CNS tumours, namely, high-grade glioma (pHGG), paediatric low-grade glioma (LGG), ependymoma (EPN), and medulloblastoma (MB). 2. has been recognised in several tumours as a potential therapeutic target. This dependency is due to the inability of cancer cells to recycle or synthesise intracellular arginine through the urea cycle pathway compared to normal cells. Whilst adult glioblastoma exhibits this dependency, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours. We used immunohistochemical (IHC) methods to stain for arginine pathway enzymes in paediatric high-grade glioma (pHGG), low-grade glioma (pLGG), ependymoma (EPN), and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser arginase (Arg1 and Arg2); recycling enzymes ornithine transcarbamoylase (OTC), argininosuccinate synthetase (ASS1), and argininosuccinate lyase (ASL); and the transporter SLC7A1. Deficiency of OTC, ASS1, and ASL was seen in 87.5%, 94%, and 79% of pHGG samples, respectively, consistent with an auxotrophic signature. Comparable result was obtained in pLGG with 96%, 93%, and 91% of tumours being deficient in ASL, ASS1, Acamprosate calcium and OTC, respectively. 79%, 88%, and 85% of MB cases were ASL, ASS1, and OTC deficient whilst ASL and OTC were deficient in 57% and 91% of EPN samples. All tumour types highly expressed SLC7A1 and Arginase, with Arg2 being the main isoform, demonstrating that they could transport and utilise arginine. Our results show that pHGG, pLGG, EPN, and MB demonstrate arginine auxotrophy based on protein expression and are likely to be susceptible to arginine depletion. Pegylated arginase (BCT-100) is currently in phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in other tumour types and IHC analysis of patient tumour samples could help identify patients likely to benefit from this treatment. 1. Introduction Paediatric central nervous system (CNS) tumours are the commonest solid tumour in childhood and account for around 25% of paediatric cancers [1]. Acamprosate calcium They are the leading cause of cancer-related death in children [2]. Despite improvements in the survival and remedy rates of other childhood cancers, the prognosis for several types of brain tumour remains poor [1]. Treatment-related morbidity is usually high with significant late effects in survivors [3]. There is therefore a need to develop kinder, effective treatments to increase survival and reduce late effects. One of the hallmarks of cancer is the ability of the Acamprosate calcium tumour cell to alter its cellular machinery to promote growth and survival [4]. One such adaptation is the Warburg effect, reported almost a century ago, wherein the cancer cell derives its energy by anaerobic glycolysis, even in the presence of oxygen [5]. Targeting the metabolic machinery of the cell through various means has since been pursued to develop Rabbit Polyclonal to BEGIN treatments for cancer. The folate antagonist drug methotrexate is one such example [6]. In recent years, there is increasing evidence that cancer cells also rewire the metabolism of amino acids [7, 8]. Amino acids are the building blocks of protein and also serve as neurotransmitters and option substrates for glycolysis and are required for nucleotide synthesis [7]. Tumour cells often exhibit specific metabolic dependencies, such as the increased requirement of certain amino acids to fuel their growth or to modulate the immune response to the tumour [9]. Exploiting unique aspects of tumour Acamprosate calcium metabolism aims to selectively attack those tumour cells, effectively avoiding normal tissue toxicity [10]. The concept of targeting amino acid metabolism has been studied for many decades, and the most successful example to date is the depletion of asparagine in the treatment of acute lymphoblastic leukaemia [11]. Arginine is usually a semiessential amino acid that plays a crucial role in cellular metabolism and homeostasis. It is central to the urea cycle and is a key precursor for polyamine and nitric oxide (NO) production [12]. During periods of stress, such as the hostile tumour microenvironment, cells are unable to meet metabolic demands for arginine. In such conditions, arginine functions as an essential amino acid, which is critical for cell survival, growth, and other Acamprosate calcium hallmarks of cancer [13] The depletion of semiessential amino acids could show lethal to those cells, thus, further delineating that this role of arginine in cancer could provide novel therapeutic opportunity. Cells obtain arginine from.