A systems-based mathematical modelling framework for investigating the effect of drugs on solid tumours
Related Experiment Video
Updated: May 26, 2026
Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
Cong Liu1, J Krishnan, Xiao Yun Xu
1Chemical Engineering and Chemical Technology, Imperial College London, South Kensington, London SW7 2AZ, UK.
Background:
Elucidating the effects of drugs on solid tumours is a highly challenging multi-level problem, since this involves many complexities associated with transport and cellular response, which in turn is characterized by highly non-linear chemical signal transduction. Appropriate systems frameworks are needed to seriously address the sources of these complexities, especially from the cellular side.
Results:
We develop a skeletal modelling framework incorporating interstitial drug transport, intracellular signal processing and cell population descriptions. The descriptions aim to appropriately capture the nature of information flow. The model is deliberately formulated to start with simple intracellular descriptions so that additional features can be incorporated in a modular fashion. Two kinds of intracellular signalling modules which describe the drug effect were considered, one a monostable switch and the other a bistable switch. Analysis of our model revealed how different drug stimuli can lead to cell killing in the tumour. Interestingly both modules considered exhibited similar trends. The effects of important parameters were also studied.
Conclusions:
We have created a predictive systems platform integrating drug transport and cellular response which can be systematically augmented to include additional layers of cellular complexity. Our results indicate that intracellular signalling models which are qualitatively different can give rise to similar behaviour to simple (and typical) stimuli, and that validating intracellular descriptions must be performed with care by considering a variety of drug stimuli.
Insights
This study presents a computational model for drug effects in solid tumors, integrating drug transport and cellular signaling. The framework reveals how different signaling pathways can lead to similar cell-killing outcomes, emphasizing careful validation.
Area of Science:
- Computational biology
- Systems biology
- Pharmacodynamics
Background:
- Drug effects in solid tumors are complex due to transport and non-linear cellular signaling.
- Existing systems frameworks struggle to address cellular complexities in tumor drug response.
Purpose of the Study:
- To develop a flexible modeling framework for simulating drug effects on solid tumors.
- To investigate how different intracellular signaling mechanisms influence tumor cell response to drugs.
Main Methods:
- Developed a skeletal modeling framework integrating interstitial drug transport, intracellular signal processing, and cell population dynamics.
- Incorporated modular intracellular signaling descriptions, including monostable and bistable switch models.
- Analyzed the impact of various drug stimuli and key parameters on tumor cell killing.
Main Results:
- The model successfully integrates drug transport and cellular response mechanisms.
- Both monostable and bistable intracellular signaling modules exhibited similar trends in cell killing.
- Identified key parameters influencing drug efficacy within the tumor microenvironment.
Conclusions:
- A predictive systems platform was created, capable of incorporating additional cellular complexity.
- Qualitatively different intracellular signaling models can produce similar responses to simple drug stimuli.
- Validation of intracellular models requires careful consideration of diverse drug stimuli.
Related Concept Videos
01:06Model Approaches for Pharmacokinetic Data: Distributed Parameter Models
The distributed parameter models are specifically designed to account for variations and differences in some drug classes. This model is particularly useful for assessing regional concentrations of anticancer or...
01:20Pharmacokinetic Models: Overview
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal assumptions,...
01:14Pharmacodynamic Models: Link Model and Systems Pharmacodynamic Model
01:26Pharmacokinetic Models: Comparison and Selection Criterion
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
01:27Pharmacodynamic Models: Overview
01:09Pharmacodynamic Models: Additive and Proportional Drug Effect Model