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Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer

In the absence of curative therapies, treatment of metastatic castrate-resistant prostate cancer (mCRPC) using currently available drugs can be improved by integrating evolutionary principles that govern proliferation of resistant subpopulations into current treatment protocols. Here we develop what...

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Autores principales: Cunningham, Jessica, Thuijsman, Frank, Peeters, Ralf, Viossat, Yannick, Brown, Joel, Gatenby, Robert, Staňková, Kateřina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723267/
https://www.ncbi.nlm.nih.gov/pubmed/33290430
http://dx.doi.org/10.1371/journal.pone.0243386
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author Cunningham, Jessica
Thuijsman, Frank
Peeters, Ralf
Viossat, Yannick
Brown, Joel
Gatenby, Robert
Staňková, Kateřina
author_facet Cunningham, Jessica
Thuijsman, Frank
Peeters, Ralf
Viossat, Yannick
Brown, Joel
Gatenby, Robert
Staňková, Kateřina
author_sort Cunningham, Jessica
collection PubMed
description In the absence of curative therapies, treatment of metastatic castrate-resistant prostate cancer (mCRPC) using currently available drugs can be improved by integrating evolutionary principles that govern proliferation of resistant subpopulations into current treatment protocols. Here we develop what is coined as an ‘evolutionary stable therapy’, within the context of the mathematical model that has been used to inform the first adaptive therapy clinical trial of mCRPC. The objective of this therapy is to maintain a stable polymorphic tumor heterogeneity of sensitive and resistant cells to therapy in order to prolong treatment efficacy and progression free survival. Optimal control analysis shows that an increasing dose titration protocol, a very common clinical dosing process, can achieve tumor stabilization for a wide range of potential initial tumor compositions and volumes. Furthermore, larger tumor volumes may counter intuitively be more likely to be stabilized if sensitive cells dominate the tumor composition at time of initial treatment, suggesting a delay of initial treatment could prove beneficial. While it remains uncertain if metastatic disease in humans has the properties that allow it to be truly stabilized, the benefits of a dose titration protocol warrant additional pre-clinical and clinical investigations.
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spelling pubmed-77232672020-12-16 Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer Cunningham, Jessica Thuijsman, Frank Peeters, Ralf Viossat, Yannick Brown, Joel Gatenby, Robert Staňková, Kateřina PLoS One Research Article In the absence of curative therapies, treatment of metastatic castrate-resistant prostate cancer (mCRPC) using currently available drugs can be improved by integrating evolutionary principles that govern proliferation of resistant subpopulations into current treatment protocols. Here we develop what is coined as an ‘evolutionary stable therapy’, within the context of the mathematical model that has been used to inform the first adaptive therapy clinical trial of mCRPC. The objective of this therapy is to maintain a stable polymorphic tumor heterogeneity of sensitive and resistant cells to therapy in order to prolong treatment efficacy and progression free survival. Optimal control analysis shows that an increasing dose titration protocol, a very common clinical dosing process, can achieve tumor stabilization for a wide range of potential initial tumor compositions and volumes. Furthermore, larger tumor volumes may counter intuitively be more likely to be stabilized if sensitive cells dominate the tumor composition at time of initial treatment, suggesting a delay of initial treatment could prove beneficial. While it remains uncertain if metastatic disease in humans has the properties that allow it to be truly stabilized, the benefits of a dose titration protocol warrant additional pre-clinical and clinical investigations. Public Library of Science 2020-12-08 /pmc/articles/PMC7723267/ /pubmed/33290430 http://dx.doi.org/10.1371/journal.pone.0243386 Text en © 2020 Cunningham et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Cunningham, Jessica
Thuijsman, Frank
Peeters, Ralf
Viossat, Yannick
Brown, Joel
Gatenby, Robert
Staňková, Kateřina
Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer
title Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer
title_full Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer
title_fullStr Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer
title_full_unstemmed Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer
title_short Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer
title_sort optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723267/
https://www.ncbi.nlm.nih.gov/pubmed/33290430
http://dx.doi.org/10.1371/journal.pone.0243386
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