Why Is Evolution Important in Cancer and What Mathematics Should Be Used to Treat Cancer? Focus on Drug Resistance

International audienceThe clinical question of drug resistance in cancer, our initial motivation to studycontinuous models of adaptive cell population dynamics, leads naturally and moregenerally to consider the cancer disease itself from an evolutionary biology view-point, a consideration without which even the best targeted therapies will likelymost often eventually fail. Among the challenging questions to mathematicianswho tackle the task of understanding this disease and optimising its treatmentare the representation of phenotypic heterogeneity of cancer cell populations andof their plasticity in response to anticancer drug insults. Such representation canbe obtained using phenotype-structured models of healthy and cancer cell popula-tions, and optimal control methods to optimise drug effects, with the perspectiveto implement them in the therapeutics of cancer, aiming at both avoiding theemergence of drug resistance in tumours and taking into account a constraint oflimiting unwanted adverse effects to healthy tissues

Computational Approaches and Analysis for a Spatio-Structural-Temporal Invasive Carcinoma Model

Spatio-temporal models have long been used to describe biological systems of cancer, but it has not been until very recently that increased attention has been paid to structural dynamics of the interaction between cancer populations and the molecular mechanisms associated with local invasion. One system that is of particular interest is that of the urokinase plasminogen activator (uPA) wherein uPA binds uPA receptors on the cancer cell surface, allowing plasminogen to be cleaved into plasmin, which degrades the extracellular matrix and this way leads to enhanced cancer cell migration. In this paper, we develop a novel numerical approach and associated analysis for spatio-structuro-temporal modelling of the uPA system for up to two-spatial and two-structural dimensions. This is accompanied by analytical exploration of the numerical techniques used in simulating this system, with special consideration being given to the proof of stability within numerical regimes encapsulating a central differences approach to approximating numerical gradients. The stability analysis performed here reveals instabilities induced by the coupling of the structural binding and proliferative processes. The numerical results expound how the uPA system aids the tumour in invading the local stroma, whilst the inhibitor to this system may impede this behaviour and encourage a more sporadic pattern of invasion.PostprintPeer reviewe

Reuniting philosophy and science to advance cancer research

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer

Reuniting philosophy and science to advance cancer research

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer

Population Modeling of Tumor Growth Curves, the Reduced Gompertz Model and Prediction of the Age of a Tumor

Quantitative analysis of tumor growth kinetics has been widely carried out using mathematical models. In the majority of cases, individual or average data were fitted. Here, we analyzed three classical models (exponential, logistic and Gom-pertz within the statistical framework of nonlinear mixed-effects modelling , which allowed us to account for inter-animal variability within a population group. We used in vivo data of subcutaneously implanted Lewis Lung carcinoma cells. While the exponential and logistic models failed to accurately fit the data, the Gompertz model provided a superior descriptive power. Moreover, we observed a strong correlation between the Gompertz parameters. Combining this observation with rigorous population parameter estimation motivated a simplification of the standard Gompertz model in a reduced Gompertz model, with only one individual parameter. Using Bayesian inference, we further applied the population methodology to predict the individual initiation times of the tumors from only three measurements. Thanks to its simplicity, the reduced Gompertz model exhibited superior predictive power. The method that we propose here remains to be extended to clinical data, but these results are promising for the personalized estimation of the tumor age given limited data at diagnosis