One-Carbon Metabolism Associated Vulnerabilities in Glioblastoma: A Review

SIMPLE SUMMARY: Glioblastoma tumours are the most malignant and common type of central nervous system tumours. Despite aggressive treatment measures, disease recurrence in patients with glioblastoma is inevitable and survival rates remain low. Glioblastoma cells, like other cancer cells, can leverage metabolic pathways to increase their rate of proliferation, maintain self-renewal, and develop treatment resistance. Furthermore, many of the metabolic strategies employed by cancer cells are similar to those employed by stem cells in order to maintain self-renewal and proliferation. One-carbon metabolism and de novo purine synthesis are metabolic pathways that are essential for biosynthesis of macromolecules and have been found to be essential for tumourigenesis. In this review, we summarize the evidence showing the significance of 1-C-mediated de novo purine synthesis in glioblastoma cell proliferation and tumourigenesis, as well as evidence suggesting the effectiveness of targeting this metabolic pathway as a therapeutic modality. ABSTRACT: Altered cell metabolism is a hallmark of cancer cell biology, and the adaptive metabolic strategies of cancer cells have been of recent interest to many groups. Metabolic reprogramming has been identified as a critical step in glial cell transformation, and the use of antimetabolites against glioblastoma has been investigated. One-carbon (1-C) metabolism and its associated biosynthetic pathways, particularly purine nucleotide synthesis, are critical for rapid proliferation and are altered in many cancers. Purine metabolism has also been identified as essential for glioma tumourigenesis. Additionally, alterations of 1-C-mediated purine synthesis have been identified as commonly present in brain tumour initiating cells (BTICs) and could serve as a phenotypic marker of cells responsible for tumour recurrence. Further research is required to elucidate mechanisms through which metabolic vulnerabilities may arise in BTICs and potential ways to therapeutically target these metabolic processes. This review aims to summarize the role of 1-C metabolism-associated vulnerabilities in glioblastoma tumourigenesis and progression and investigate the therapeutic potential of targeting this pathway in conjunction with other treatment strategies.