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

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.

Interrogating and Quantifying In Vitro Cancer Drug Pharmacodynamics via Agent-Based and Bayesian Monte Carlo Modelling.

The effectiveness of chemotherapy in cancer cell regression is often limited by drug resistance, toxicity, and neoplasia heterogeneity. However, due to the significant complexities entailed by the many cancer growth processes, predicting the impact of interference and symmetry-breaking mechanisms is a difficult problem. To quantify and understand more about cancer drug pharmacodynamics, we combine in vitro with in silico cancer models. The anti-proliferative action of selected cytostatics is interrogated on human colorectal and breast adenocarcinoma cells, while an agent-based computational model is employed to reproduce experiments and shed light on the main therapeutic mechanisms of each chemotherapeutic agent. Multiple drug administration scenarios on each cancer cell line are simulated by varying the drug concentration, while a Bayesian-based method for model parameter optimisation is employed. Our proposed procedure of combining in vitro cancer drug screening with an in silico agent-based model successfully reproduces the impact of chemotherapeutic drugs in cancer growth behaviour, while the mechanisms of action of each drug are characterised through model-derived probabilities of cell apoptosis and division. We suggest that our approach could form the basis for the prospective generation of experimentally-derived and model-optimised pharmacological variables towards personalised cancer therapy.

Investigating the reference domain influence in personalised models of cardiac mechanics : Effect of unloaded geometry on cardiac biomechanics.

A major concern in personalised models of heart mechanics is the unknown zero-pressure domain, a prerequisite for accurately predicting cardiac biomechanics. As the reference configuration cannot be captured by clinical data, studies often employ in-vivo frames which are unlikely to correspond to unloaded geometries. Alternatively, zero-pressure domain is approximated through inverse methodologies, which, however, entail assumptions pertaining to boundary conditions and material parameters. Both approaches are likely to introduce biases in estimated biomechanical properties; nevertheless, quantification of these effects is unattainable without ground-truth data. In this work, we assess the unloaded state influence on model-derived biomechanics, by employing an in-silico modelling framework relying on experimental data on porcine hearts. In-vivo images are used for model personalisation, while in-situ experiments provide a reliable approximation of the reference domain, creating a unique opportunity for a validation study. Personalised whole-cycle cardiac models are developed which employ different reference domains (image-derived, inversely estimated) and are compared against ground-truth model outcomes. Simulations are conducted with varying boundary conditions, to investigate the effect of data-derived constraints on model accuracy. Attention is given to modelling the influence of the ribcage on the epicardium, due to its close proximity to the heart in the porcine anatomy. Our results find merit in both approaches for dealing with the unknown reference domain, but also demonstrate differences in estimated biomechanical quantities such as material parameters, strains and stresses. Notably, they highlight the importance of a boundary condition accounting for the constraining influence of the ribcage, in forward and inverse biomechanical models.