Combining Hypoxia-Activated Prodrugs and Radiotherapy in silico: Impact of Treatment Scheduling and the Intra-Tumoural Oxygen Landscape

Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments. We here demonstrate that both the intra-tumoural oxygen landscape and treatment scheduling of HAP-radiation combination therapies influence treatment responses in silico. Our in silico framework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data.