DePillis2003 - The dynamics of an optimally controlled tumor model: A case study
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ABSTRACT:
SUBMITTER: 
Mohammad Umer Sharif Shohan
PROVIDER: BIOMD0000000909 | BioModels | 2024-09-02
REPOSITORIES: BioModels
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| BIOMD0000000909?filename=dePillis2003.cps | Other | |||
| BIOMD0000000909?filename=dePillis2003.sedml | Other | |||
| BIOMD0000000909?filename=dePillis2003.xml | Xml |
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A B S T R A C T
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Dept. of Mathematics and Statistics, Southern Illinois University Edwardsville, Edwardsville, Illinois 62026-1653, USA. uledzew@siue.edu
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Project description:Abstract
We investigate a mathematical model of tumor–immune interactions with chemotherapy, and strategies
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Author information
Abstract
Metronomic dosing of chemotherapy-defined as frequent administration at lower doses-has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy.
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Project description:A minimally parameterized mathematical model for low-dose metronomic
chemotherapy is formulated that takes into account angiogenic signaling between
the tumor and its vasculature and tumor inhibiting effects of tumor-immune system
interactions. The dynamical equations combine a model for tumor development under
angiogenic signaling formulated by Hahnfeldt et al. with a model for tumor-immune
system interactions by Stepanova. The dynamical properties of the model are analyzed.
Depending on the parameter values, the system encompasses a variety of medically
realistic scenarios that range from cases when (i) low-dose metronomic chemotherapy
is able to eradicate the tumor (all trajectories converge to a tumor-free equilibrium
point) to situations when (ii) tumor dormancy is induced (a unique, globally asymp-
totically stable benign equilibrium point exists) to (iii) multi-stable situations that have
both persistent benign and malignant behaviors separated by the stable manifold of
an unstable equilibrium point and finally to (iv) situations when tumor growth can-
not be overcome by low-dose metronomic chemotherapy. The model forms a basis
for a more general study of chemotherapy when the main components of a tumor’s
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