Role of hypoxia-activated prodrugs in combination with radiation therapy: An in silico approach.

Cameron Meaney,1 Department Of Applied Mathematics, University Of Waterloo, Waterloo, Canada , ,Ludwig J Dubois,Mohammad Kohande,Philippe Lambin,Gibin G Powathil,Ala Yaromina

doi:10.3934/mbe.2019312

Cameron Meaney, 1 Department Of Applied Mathematics, University Of Waterloo, Waterloo, Canada + Show 6 more

Open Access

https://doi.org/10.3934/mbe.2019312

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Abstract

Tumour hypoxia has been associated with increased resistance to various cancer treatments, particularly radiation therapy. Conversely, tumour hypoxia is a validated and ideal target for guided cancer drug delivery. For this reason, hypoxia-activated prodrugs (HAPs) have been developed, which remain inactive in the body until in the presence of tissue hypoxia, allowing for an activation tendency in hypoxic regions. We present here an experimentally motivated mathematical model predicting the effectiveness of HAPs in a variety of clinical settings. We first examined HAP effectiveness as a function of the amount of tumour hypoxia and showed that the drugs have a larger impact on tumours with high levels of hypoxia. We then combined HAP treatment with radiation to examine the effects of combination therapies. Our results showed radiation-HAP combination therapies to be more effective against highly hypoxic tumours. The analysis of combination therapies was extended to consider schedule sequencing of the combination treatments. These results suggested that administering HAPs before radiation was most effective in reducing total cell number. Finally, a sensitivity analysis of the drug-related parameters was done to examine the effect of drug diffusivity and enzyme abundance on the overall effectiveness of the drug. Altogether, the results highlight the importance of the knowledge of tumour hypoxia levels before administration of HAPs in order to ensure positive results.

Highlights

Tumourigenesis is a complex, multi-step process which leads to the formation of solid malignancies
These results show that depending on the tumour type, a combination treatment of radiation combined with hypoxia-activated prodrugs (HAPs) can be very effective
We have developed here a spatio-temporal mathematical model to describe the effects of HAPs, alone and in combination with radiation, on a growing tumour

Summary

Introduction

Tumourigenesis is a complex, multi-step process which leads to the formation of solid malignancies. A critical step in this process is angiogenesis in which tumours develop their own vasculature and blood supply. Angiogenesis is carefully self-regulated and tightly controlled, whereas in tumours, the vessels are structurally and functionally abnormal. They are often characterized by defective endothelia, basement membranes, and pericyte coverage leading to inefficient nutrient delivery to tumour cells despite a high global blood flow in the environment [1]. The poor delivery of oxygen results in regions of severe hypoxia—a trait observed in most solid malignancies [2, 3]. Tumour hypoxia has been linked to the increase of many cancerous behaviors such as genomic instability, malignant progression, and metastasis formation [4, 5]

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