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Independent Drug Action in Combination Therapy: Implications for Precision Oncology

Combination therapies are superior to monotherapy for many cancers. This advantage was historically ascribed to the ability of combinations to address tumor heterogeneity, but synergistic interaction is now a common explanation as well as a design criterion for new combinations. We review evidence t...

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Detalles Bibliográficos
Autores principales: Plana, Deborah, Palmer, Adam C., Sorger, Peter K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904281/
https://www.ncbi.nlm.nih.gov/pubmed/34983746
http://dx.doi.org/10.1158/2159-8290.CD-21-0212
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author Plana, Deborah
Palmer, Adam C.
Sorger, Peter K.
author_facet Plana, Deborah
Palmer, Adam C.
Sorger, Peter K.
author_sort Plana, Deborah
collection PubMed
description Combination therapies are superior to monotherapy for many cancers. This advantage was historically ascribed to the ability of combinations to address tumor heterogeneity, but synergistic interaction is now a common explanation as well as a design criterion for new combinations. We review evidence that independent drug action, described in 1961, explains the efficacy of many practice-changing combination therapies: it provides populations of patients with heterogeneous drug sensitivities multiple chances of benefit from at least one drug. Understanding response heterogeneity could reveal predictive or pharmacodynamic biomarkers for more precise use of existing drugs and realize the benefits of additivity or synergy. SIGNIFICANCE: The model of independent drug action represents an effective means to predict the magnitude of benefit likely to be observed in new clinical trials for combination therapies. The “bet-hedging” strategy implicit in independent action suggests that individual patients often benefit from only a subset—sometimes one—of the drugs in a combination. Personalized, targeted combination therapy, consisting of agents likely to be active in a particular patient, will increase, perhaps substantially, the magnitude of therapeutic benefit. Precision approaches of this type will require a better understanding of variability in drug response and new biomarkers, which will entail preclinical research on diverse panels of cancer models rather than studying drug synergy in unusually sensitive models.
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spelling pubmed-89042812022-09-01 Independent Drug Action in Combination Therapy: Implications for Precision Oncology Plana, Deborah Palmer, Adam C. Sorger, Peter K. Cancer Discov Reviews Combination therapies are superior to monotherapy for many cancers. This advantage was historically ascribed to the ability of combinations to address tumor heterogeneity, but synergistic interaction is now a common explanation as well as a design criterion for new combinations. We review evidence that independent drug action, described in 1961, explains the efficacy of many practice-changing combination therapies: it provides populations of patients with heterogeneous drug sensitivities multiple chances of benefit from at least one drug. Understanding response heterogeneity could reveal predictive or pharmacodynamic biomarkers for more precise use of existing drugs and realize the benefits of additivity or synergy. SIGNIFICANCE: The model of independent drug action represents an effective means to predict the magnitude of benefit likely to be observed in new clinical trials for combination therapies. The “bet-hedging” strategy implicit in independent action suggests that individual patients often benefit from only a subset—sometimes one—of the drugs in a combination. Personalized, targeted combination therapy, consisting of agents likely to be active in a particular patient, will increase, perhaps substantially, the magnitude of therapeutic benefit. Precision approaches of this type will require a better understanding of variability in drug response and new biomarkers, which will entail preclinical research on diverse panels of cancer models rather than studying drug synergy in unusually sensitive models. American Association for Cancer Research 2022-03-01 2022-03-08 /pmc/articles/PMC8904281/ /pubmed/34983746 http://dx.doi.org/10.1158/2159-8290.CD-21-0212 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Reviews
Plana, Deborah
Palmer, Adam C.
Sorger, Peter K.
Independent Drug Action in Combination Therapy: Implications for Precision Oncology
title Independent Drug Action in Combination Therapy: Implications for Precision Oncology
title_full Independent Drug Action in Combination Therapy: Implications for Precision Oncology
title_fullStr Independent Drug Action in Combination Therapy: Implications for Precision Oncology
title_full_unstemmed Independent Drug Action in Combination Therapy: Implications for Precision Oncology
title_short Independent Drug Action in Combination Therapy: Implications for Precision Oncology
title_sort independent drug action in combination therapy: implications for precision oncology
topic Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904281/
https://www.ncbi.nlm.nih.gov/pubmed/34983746
http://dx.doi.org/10.1158/2159-8290.CD-21-0212
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