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Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies

The discovery of small molecules targeted to specific oncogenic pathways has revolutionized anti-cancer therapy. However, such therapy often fails due to the evolution of acquired resistance. One long-standing question in clinical cancer research is the identification of optimum therapeutic administ...

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Detalles Bibliográficos
Autores principales: Foo, Jasmine, Michor, Franziska
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766072/
https://www.ncbi.nlm.nih.gov/pubmed/19893626
http://dx.doi.org/10.1371/journal.pcbi.1000557
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author Foo, Jasmine
Michor, Franziska
author_facet Foo, Jasmine
Michor, Franziska
author_sort Foo, Jasmine
collection PubMed
description The discovery of small molecules targeted to specific oncogenic pathways has revolutionized anti-cancer therapy. However, such therapy often fails due to the evolution of acquired resistance. One long-standing question in clinical cancer research is the identification of optimum therapeutic administration strategies so that the risk of resistance is minimized. In this paper, we investigate optimal drug dosing schedules to prevent, or at least delay, the emergence of resistance. We design and analyze a stochastic mathematical model describing the evolutionary dynamics of a tumor cell population during therapy. We consider drug resistance emerging due to a single (epi)genetic alteration and calculate the probability of resistance arising during specific dosing strategies. We then optimize treatment protocols such that the risk of resistance is minimal while considering drug toxicity and side effects as constraints. Our methodology can be used to identify optimum drug administration schedules to avoid resistance conferred by one (epi)genetic alteration for any cancer and treatment type.
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spelling pubmed-27660722009-11-06 Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies Foo, Jasmine Michor, Franziska PLoS Comput Biol Research Article The discovery of small molecules targeted to specific oncogenic pathways has revolutionized anti-cancer therapy. However, such therapy often fails due to the evolution of acquired resistance. One long-standing question in clinical cancer research is the identification of optimum therapeutic administration strategies so that the risk of resistance is minimized. In this paper, we investigate optimal drug dosing schedules to prevent, or at least delay, the emergence of resistance. We design and analyze a stochastic mathematical model describing the evolutionary dynamics of a tumor cell population during therapy. We consider drug resistance emerging due to a single (epi)genetic alteration and calculate the probability of resistance arising during specific dosing strategies. We then optimize treatment protocols such that the risk of resistance is minimal while considering drug toxicity and side effects as constraints. Our methodology can be used to identify optimum drug administration schedules to avoid resistance conferred by one (epi)genetic alteration for any cancer and treatment type. Public Library of Science 2009-11-06 /pmc/articles/PMC2766072/ /pubmed/19893626 http://dx.doi.org/10.1371/journal.pcbi.1000557 Text en Foo, Michor. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Foo, Jasmine
Michor, Franziska
Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies
title Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies
title_full Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies
title_fullStr Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies
title_full_unstemmed Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies
title_short Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies
title_sort evolution of resistance to targeted anti-cancer therapies during continuous and pulsed administration strategies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766072/
https://www.ncbi.nlm.nih.gov/pubmed/19893626
http://dx.doi.org/10.1371/journal.pcbi.1000557
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