Glucose metabolism in cancer: heterogeneity and potentials for targeting in patients

Cancer cells can be distinguished from non-cancer cells by acquired characteristics, often referred to as the hallmarks of cancer. One of these hallmarks is metabolic reprogramming, which is essential to meet energy requirements, synthesise building blocks and maintain the redox balance of rapidly dividing cells. The best-known metabolic adaptation of cancer cells is aerobic glycolysis. This is defined as increased glucose uptake and high glycolysis rates despite the presence of sufficient oxygen. The metabolic characteristics of tumour cells and their microenvironment are considered important for understanding cancer development and treatment resistance, and are of interest as treatment targets. To date, translation of the interesting preclinically observed anticancer effects of glucose metabolism inhibitors into the clinic has not yet been successful. This translation may be supported by the development of tools for characterising metabolic hallmarks in patient tumours. Therefore, the research described in this thesis aimed to improve understanding of glucose metabolism in human tumours through characterisation and modulation of specific metabolic pathways, and by studying metabolic heterogeneity in tumours of cancer patients. We investigated heterogeneity of glucose uptake in non-small cell lung cancer tumour lesions and heterogeneity of expression patterns of glucose metabolism-related proteins in glioblastoma and high-grade serous ovarian cancer patient tumours. Furthermore, we studied the effects of inhibiting glycogen degradation, alone and in combination with radiotherapy, on glioblastoma cell growth and studied the subsequent intracellular effects. Lastly, we determined outcome of patients with metastatic melanoma experiencing solitary progression after initial response to immune checkpoint inhibition and described the role of local therapy in this setting