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Spatial structure impacts adaptive therapy by shaping intra-tumoral competition

View ORCID ProfileMaximilian A. R. Strobl, View ORCID ProfileJill Gallaher, View ORCID ProfileJeffrey West, Mark Robertson-Tessi, Philip K. Maini, View ORCID ProfileAlexander R. A. Anderson
doi: https://doi.org/10.1101/2020.11.03.365163
Maximilian A. R. Strobl
1Wolfson Centre for Mathematical Biology, University of Oxford, Oxford, UK
2Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center Tampa, USA
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  • ORCID record for Maximilian A. R. Strobl
Jill Gallaher
2Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center Tampa, USA
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Jeffrey West
2Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center Tampa, USA
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Mark Robertson-Tessi
2Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center Tampa, USA
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Philip K. Maini
1Wolfson Centre for Mathematical Biology, University of Oxford, Oxford, UK
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Alexander R. A. Anderson
2Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center Tampa, USA
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  • ORCID record for Alexander R. A. Anderson
  • For correspondence: alexander.anderson@moffitt.org
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Abstract

Background Adaptive therapy aims to tackle cancer drug resistance by leveraging intra-tumoural competition between drug-sensitive and resistant cells. Motivated by promising results in prostate cancer there is growing interest in extending this approach to other cancers. Here we present a theoretical study of intra-tumoural competition during adaptive therapy, to identify under which circumstances it will be superior to aggressive treatment, and how it can be improved through combination treatment;

Methods We study a 2-D, on-lattice, agent-based tumour model. We examine the impact of different micro-environmental factors on the comparison between continuous drug administration and the adaptive schedule pioneered in the first-in-human clinical trial.

Results We show that the degree of crowding, the initial resistance fraction, the presence of possible resistance costs, and the rate of tumour cell turnover are key determinants of the benefit of adaptive therapy. Subsequently, we investigate whether combination with treatments which amplify proliferation or which target cell turnover can prolong tumour control. While the former increases competition, we find that only the latter can robustly improve time to progression;

Conclusion Our work helps to identify selection factors for adaptive therapy and provides stepping stones towards the rational design of multi-drug adaptive regimens.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† These authors jointly supervised this work.

  • Abbreviations

    ABM
    Agent-based model
    ODE
    Ordinary differential equation
    TTP
    Time to progression
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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    Posted November 04, 2020.
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    Spatial structure impacts adaptive therapy by shaping intra-tumoral competition
    Maximilian A. R. Strobl, Jill Gallaher, Jeffrey West, Mark Robertson-Tessi, Philip K. Maini, Alexander R. A. Anderson
    bioRxiv 2020.11.03.365163; doi: https://doi.org/10.1101/2020.11.03.365163
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    Spatial structure impacts adaptive therapy by shaping intra-tumoral competition
    Maximilian A. R. Strobl, Jill Gallaher, Jeffrey West, Mark Robertson-Tessi, Philip K. Maini, Alexander R. A. Anderson
    bioRxiv 2020.11.03.365163; doi: https://doi.org/10.1101/2020.11.03.365163

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