The Tumour Microenvironment, and the new Possibilities PhysiCell Offers in Precision Medicine

What is Precision Medicine

Personalized medicine (aka precision medicine) is often defined as

a medical model using characterisation of individuals’ phenotypes and genotypes (e.g. molecular profiling, medical imaging, lifestyle data) for tailoring the right therapeutic strategy for the right person at the right time, and/or to determine the predisposition to disease and/or to deliver timely and targeted prevention” (1).

Over the past several decades a large array of therapeutic approaches has been developed leading to multimodal treatment options that usually include targeted therapy combined with radiation and surgery.

Targeted therapy is an essential part of precision medicine. While precision medicine deals with the person (with its disease history, demographic characteristics, etc.), targeted therapy is focused on identifying and attacking precise molecular targets in a tumour.  The development of targeted therapies is especially prominent in breast cancer treatment, where a number of novel therapies have been developed (for a review see for example 2, 3).

While precision medicine deals with the person (with its disease history, demographic characteristics, etc.), targeted therapy is focused on identifying and attacking precise molecular targets in a tumour

The aim of targeted therapy is to act on specific molecular targets, in order to attack certain types of cancer cells. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet

Where are we now with Targeted Therapies

To develop targeted therapies, the first step is to identify suitable targets i.e molecules that are involved in the growth, spread and progression of a tumour. In the current landscape it is usually done in three ways:

•       identification of overexpressed proteins specific to cancer cells;

•       identification of cancer-specific mutant proteins that are involved in cancer progression, and

•       search for chromosome instabilities that are exclusive for cancer cells.

The Problem with Cell-specific Targets

However, all these approaches do not consider the whole tumour architecture. They are exclusively focused on searching for cell-specific targets.

That would not be the problem if the efficacy of treatments would be at the desired level. Indeed, initial treatment is often remarkably efficient. However, if the initial treatment does not fully eradicate all cancer cells, tumours in a large majority of patients develop drug resistance as treatment proceeds (4).

Resistance relies on the so-called tumour microenvironment; i.e., the existence of different cell types divided into functionally different subpopulations whose spatial distribution and the relative ratio are uneven, unpredictable and “personalized” – no two tumours, even of the same type, have the same microenvironment.

 If the initial treatment does not fully eradicate all cancer cells, tumours in a large majority of patients develop drug resistance as treatment proceeds

Heterogeneity of the tumour microenvironment and its influence on the development of drug resistance has been extensively covered (see for example 5,6,7). However, despite accumulated knowledge in the last decade, we are yet to witness a therapy regimen that takes into account the spatial composition of a tumour.

To some extent it is understandable. Studying fine details of the tumour microenvironment and how it influences drug penetration and efficacy is extremely challenging. To make a breakthrough in this domain, a close collaboration between mathematical modelling and wet-lab experiments is necessary. By simulating fine-grained dynamics not reachable by standard wet-lab experiments, mathematical modelling can be of enormous help by both testing hypotheses and informing the design of future experiments (see for example 8, 9).

To make a breakthrough in this domain, a close collaboration between mathematical modelling and wet-lab experiments is necessary

New Possibilities with PhysiCell

One very promising platform for simulating the role of the microenvironment in tumour growth and drug resistance is PhysiCell (10). It is a multiscale, agent-based modelling platform, where chemicals are modelled via mass kinetics equations while each cell can be represented as a separate entity with distinct properties. Recently it has been applied to simulate the effect of functionalized nanoparticles on tumour (11,12).

Applying such a multiscale simulation approach to modelling tumour microenvironment will offer important insights to dynamics of drug-tumour interplay once a drug leaves the circulation and start penetrating into tumour tissue.

Most importantly we can analyse the fine-grained time evolution of interplay between drug penetration and metabolic and communication feedbacks between tumour cells induced by such penetration. With that knowledge, we will be in a much better position to understand the influence of tumour internal architecture on the efficacy of drug treatment.

References

  1. https://ec.europa.eu/info/research-and-innovation/research-area/health-research-and-innovation/personalised-medicine_en
  2. https://doi.org/10.1016/j.soc.2019.08.004,
  3. https://doi.org/10.1016/j.biopha.2020.110009
  4. http://dx.doi.org/10.20517/cdr.2019.10
  5. https://med.stanford.edu/curtislab.html
  6. https://dx.doi.org/10.1016%2Fj.drup.2012.01.006
  7. https://doi.org/10.18632/oncotarget.13907
  8. https://doi.org/10.1016/j.biosystems.2021.104385
  9. https://dx.doi.org/10.1200%2FCCI.19.00010
  10. https://doi.org/10.1371/journal.pcbi.1005991
  11. https://doi.org/10.1038/s41524-020-00366-8,
  12. https://doi.org/10.1038/s41524-021-00614-5

Leave a Comment

Your email address will not be published. Required fields are marked *