In Silico Investigations of Multi-Drug Adaptive Therapy Protocols
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Purpose
2.2. Entities, State Variables, and Scales
2.3. Process Overview and Scheduling
2.4. Design Concepts
2.4.1. Basic Principles
2.4.2. Emergence
2.4.3. Adaptation
2.4.4. Objectives
2.4.5. Learning
2.4.6. Prediction
2.4.7. Sensing
2.4.8. Interaction
2.4.9. Stochasticity
2.4.10. Collectives
2.4.11. Observation
2.5. Initialization
2.6. Input Data
2.7. Submodels
2.7.1. Cell Death
2.7.2. Cell Division
2.7.3. Competition for Space
2.7.4. Mutation
2.7.5. Drug Dynamics (Diffusion and Metabolism)
2.7.6. Drug Protocols
Standard Treatment (ST)
DM Cocktail Tandem
DM Ping-Pong Alternate Every Cycle
DM Ping-Pong on Progression
FD Dose-Skipping/Drug Holiday
FD Intermittent
3. Results
3.1. Dose Modulation Adaptive Therapy Protocols with Two Drugs Leads to Increased Time to Progression (TTP) Relative to Standard Treatment (ST) at Maximum Tolerated Dose
3.2. Greater Fitness Costs for Resistant Cells Increases the TTP for Adaptive Therapy
3.3. Higher Levels of Cell Turnover Increases the Efficacy of Adaptive Therapy
3.4. Cell Replacement Increases the TTP with Adaptive Therapy
3.5. Adaptive Therapy Works Better If Smaller Changes in the Tumor Burden Trigger a Change in Dose
3.6. For Dose Modulation Regimens, the Amount by Which the Drug Dose Is Changed (Delta Dose) Has Little Effect on the Success of Adaptive Therapy
3.7. Dose Modulation Adaptive Therapy Works Best When Frequent Treatment Vacations Are Allowed
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameter | Value |
---|---|
Cell division rate: doubly sensitive | 0.06 per hour |
Cell division rate: resistant to drug 1 | 0.04 per hour |
Cell division rate: resistant to drug 2 | 0.04 per hour |
Cell division rate: doubly resistant | 0.02 per hour |
Background death rate | 0.01 per hour |
Replacement probability | 0.5 |
Delta Tumor | 10% |
Delta Dose | 50% |
Probability of death due to drug 1 potency (Ψ1) | 0.04 per unit drug concentration |
Probability of death due to drug 2 potency (Ψ2) | 0.04 per unit drug concentration |
Maximum tolerated dose (MTD) | 5.0 units for a single drug. See Section 2.7.6 for MTD under combination therapies. |
Minimum drug dose | 0.5 units |
Drug on time | 1 h |
Frequency of drug application | Once every 24 h |
Check tumor burden | Every 3 days |
Drug decay | 10% per hour |
Drug diffusion rate | 2.0 |
Tumor size triggering treatment | Tumor burden is 50% or more of the carrying capacity |
Mutation rate | 10−3 per cell division |
Measurement noise standard deviation (SD) | 5 cells |
Total grid size | 100 by 100 |
Duration of simulation | 5000 h |
Stop dosing/initiate treatment vacation when (DM protocols only): | Tumor burden is less than or equal to 25% of carrying capacity |
Cell Types | Doubling Time |
---|---|
Doubly sensitive | 13.86 h |
Resistant to drug 1 | 23.1 h |
Resistant to drug 2 | 23.1 h |
Doubly resistant | 69.3 h |
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Thomas, D.S.; Cisneros, L.H.; Anderson, A.R.A.; Maley, C.C. In Silico Investigations of Multi-Drug Adaptive Therapy Protocols. Cancers 2022, 14, 2699. https://doi.org/10.3390/cancers14112699
Thomas DS, Cisneros LH, Anderson ARA, Maley CC. In Silico Investigations of Multi-Drug Adaptive Therapy Protocols. Cancers. 2022; 14(11):2699. https://doi.org/10.3390/cancers14112699
Chicago/Turabian StyleThomas, Daniel S., Luis H. Cisneros, Alexander R. A. Anderson, and Carlo C. Maley. 2022. "In Silico Investigations of Multi-Drug Adaptive Therapy Protocols" Cancers 14, no. 11: 2699. https://doi.org/10.3390/cancers14112699