Glucose and glycogen metabolism in cancer:potentials for intervention and patient selection

Metabolic alterations enable cancer cells to proliferate rapidly by providing sufficient biomolecules, energy and reducing equivalents for cell division and growth. Furthermore, high glucose consumption by the tumour and excretion of waste metabolites affect cells in the tumour microenvironment. As a consequence, anti-tumour immune responses can be hampered. Specific metabolic alterations can also underlie acquired resistance to currently used targeted therapies. Therefore, targeting cancer metabolism may be an attractive novel therapeutic strategy. Nevertheless, bringing anti-cancer metabolic therapies to the clinic has been hampered by a lack of suitable targets, disappointing efficacy, and considerable toxicity.In the work described in this thesis, we aimed to identify novel therapeutic targets in the glucose and glycogen metabolism of solid tumours and to evaluate clinical markers that reflect tumour glucose metabolism in patients. In the first part of the thesis, the enzyme glycogen synthase 1, important for glycogen synthesis, was identified as a novel target-of-interest in breast and ovarian cancer cells. In the second part, we used quantitative PET/CT scanning with the glucose analogue 18F-fluorodeoxyglucose and immunohistochemical target expression in patient tumours, which revealed substantial differences in tumour glucose metabolism in patients. Together, the insights from this thesis provide leads for novel drug targets and potential tools for patient selection which may guide future studies that evaluate drugs targeting cancer’s glucose and glycogen metabolism