A major challenge in cancer therapy is to develop therapeutic agents that selectively target tumour cells. One avenue towards the development of more selective cancer therapies is to exploit the unique physiological properties of solid tumours using prodrug approaches. Hypoxia (low oxygen tension) generated as a result of a poor and inefficient neovasculature is a characteristic feature of many solid tumours and is associated with the development of an aggressive phenotype and resistance to chemo- and radiotherapy. Furthermore, tumour cells exposed to hypoxia release a range of potent angiogenic factors that stimulates the development of new capillary-like vessels, allowing the tumour to continue to proliferate. Whilst problematical for conventional therapies, hypoxia is regarded as a valid target for drug development and this project is focused on the design and development of innovative chemical and biological tools that have potential to be translated into novel therapeutics to treat hypoxic solid tumours.
Primary focus will be on the discovery of new hypoxia-activated prodrugs (HAPs) and antibody-based fusion proteins labelled with a fluorophore or a cytotoxin that can be used to explore solid tumour microenvironment in vitro (3D spheroids) and in vivo (xenografts). In order to investigate the influence of HAPs in angiogenesis (formation of blood vessels), co-culture of 3D spheroids in combination with endothelial cells will be set up under normoxic and hypoxic conditions. Both efficacy and toxicity of HAPs will be assessed by quantification of tubule formation. Through external collaboration there is also an option to investigate novel therapeutics in combination with radiotherapy.