The role of autophagy in clinical practice.

Resisting cell death is one of the six hallmarks of cancer. Autophagy is a highly adaptable metabolic process that plays an important role in stressful conditions, such as nutrient deprivation and hypoxia. In these conditions, it is becoming evident that autophagy protects cells, by providing an alternative energy source and by eliminating dysfunctional organelles or proteins. In tumourigenesis, autophagy plays a dual role, which may be related to the different stages in cancer development. The autophagy-mediated removal of damaged proteins and organelles may prevent cancer initiation by limiting tissue inflammation. In contrast, autophagy has been shown to allow established tumours to survive in nutrient-deprived or hypoxic conditions during cancer progression. Key regulators of the autophagy pathway are modulated or aberrantly expressed in cancer and modulating autophagy is an attractive concept for cancer therapy. The difficulties, however, lie in the complexity of the crosstalk between apoptosis and autophagy and the lack of robust tissue biomarkers and in vivo assessment of autophagic flux. Currently there are 19 clinical trials in both solid and haematogenous cancers investigating the efficacy and toxicity of adding an autophagy inhibitor to standard treatment. Hydroxychloroquine, a drug routinely used in the treatment of malaria and autoimmune disorders, is the most common autophagy inhibitor under investigation due to its more favourable toxicity profile. This overview summarises the role of autophagy in cancer initiation, progression and resistance to treatment and thereby the therapeutic benefit that may be gained by modulating its effects.