A major event in cancer progression is angiogenesis, the formation of new blood vessels from the existing vasculature, which provide a means for supplying nutrients and oxygen to a starving growing tumour. Thus, in order to better understand the governing biophysical processes of cancer growth and angiogenesis, we are developing physiologically representative multiscale in silico models with which to compare to experimental data. Our progress was published in a series of open-access papers.
However, due to the pivotal role of angiogenesis, significant effort has been devoted to the development of anti-angiogenic (AA) drugs. They can have a direct effect, by hindering the formation of new vessels and reducing the density of the existing vasculature. Importantly, AA drugs can also have indirect benefits, by enhancing drug delivery. Despite their potential, AA therapies have seen limited use in the clinic. This could be attributed to our limited understanding of their many mechanisms of action (reduction in vascular density, vascular normalization, stopping the formation of new vessels) and their intricate interaction when AA drugs are administered as a monotherapy or in combination with chemotherapy.
In silico modelling offers great advantages to systematically investigating the role of individual mechanisms of action of AA drugs in tumour progression. In our project, CancerMoDeration, we have developed a multi-scale in-silico model of tumour growth encompassing angiogenesis, tissue biomechanics and blood flow, along with the delivery of chemotherapeutic drugs. Our framework is also used to investigate several mechanisms of action of AA drugs, including the reduction of vascular density and vascular normalization. Moreover, AA drugs are considered in combination with chemotherapy, whereby the dosage and timing of drug administration varied.
Our results highlight which therapeutic strategies (e.g., combinatory treatment protocols versus monotherapies) are more efficacious, while they also demonstrate the potential of our in silico framework being used as a test-bed for evaluating treatment strategies in a non-invasive and cost-effective manner – with the long-term vision goal being the use of in silicotrials towards animal testing reduction.
Selected relevant works:
Hadjicharalambous et al. 2021. European Society of Biomechanics, Milan, Italy.
Vavourakis & Wijeratne 2019. Royal Society Interface Focus, doi: 10.1098/rsfs.2018.0063
Vavourakis et al. 2018. PLOS Computational Biology, doi: 10.1371/journal.pcbi.1006460
Vavourakis et al. 2017. PLOS Computational Biology, doi: 10.1371/journal.pcbi.1005259
Snapshot taken from a time-lapse video, produced using optical frequency domain imaging, of an MCaIV tumour implanted in the dorsal skinfold chamber (Source: https://doi.org/10.1038/nm.1971). From this sequence of in vivo microscopy image data of the growing tumour (https://static-content.springer.com/esm/art%3A10.1038%2Fnm.1971/MediaObjects/41591_2009_BFnm1971_MOESM2_ESM.mov) neo-vascularization is evident at the tumour site while also vessel collapse (lack of vessels) can be seen inside the tumour core.