Combined anti-angiogenic and cytotoxic treatment of a solid tumour: in silico investigation of a xenograft animal model’s digital twin

Abstract

Anti-angiogenic (AA) treatments have received significant research interest due to the key role of angiogenesis in cancer progression. AA agents can have a strong effect on cancer regression, by blocking new vessels and reducing the density of the existing vasculature. Moreover, in a process termed vascular normalisation, AA drugs can improve the abnormal structure and function of the tumour vasculature, enhancing the delivery of chemotherapeutics to the tumour site. Despite their promising potential, an improved understanding of AA treatments is necessary to optimise their administration as a monotherapy or in combination with other cancer treatments. In this work we present an in silico multiscale cancer model which is used to systematically interrogate the role of individual mechanisms of action of AA drugs in tumour regression. Focus is placed on the reduction of vascular density and on vascular normalisation through a parametric study, which are considered either as monotherapies or in combination with conventional/ metronomic chemotherapy. The model is specified to data from a mammary carcinoma xenograft in immunodeficient mice, to enhance the physiological relevance of model predictions. Our results suggest that conventional chemotherapy might be more beneficial when combined with AA treatments, hindering tumour growth without causing excessive damage on healthy tissue. Notably, metronomic chemotherapy has shown significant potential in stopping tumour growth with minimal toxicity, even as a monotherapy. Our findings underpin the potential of our in silico framework for non-invasive and cost-effective evaluation of treatment strategies, which can enhance our understanding of combined therapeutic strategies and contribute towards improving cancer treatment management.