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Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization

Implementation of effective cancer treatment strategies requires consideration of how the spatiotemporal heterogeneities within the tumor microenvironment (TME) influence tumor progression and treatment response. Here, we developed a multi-scale three-dimensional mathematical model of the TME to sim...

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Detalles Bibliográficos
Autores principales: Nikmaneshi, Mohammad R., Jain, Rakesh K., Munn, Lance L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10249820/
https://www.ncbi.nlm.nih.gov/pubmed/37289729
http://dx.doi.org/10.1371/journal.pcbi.1011131
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author Nikmaneshi, Mohammad R.
Jain, Rakesh K.
Munn, Lance L.
author_facet Nikmaneshi, Mohammad R.
Jain, Rakesh K.
Munn, Lance L.
author_sort Nikmaneshi, Mohammad R.
collection PubMed
description Implementation of effective cancer treatment strategies requires consideration of how the spatiotemporal heterogeneities within the tumor microenvironment (TME) influence tumor progression and treatment response. Here, we developed a multi-scale three-dimensional mathematical model of the TME to simulate tumor growth and angiogenesis and then employed the model to evaluate an array of single and combination therapy approaches. Treatments included maximum tolerated dose or metronomic (i.e., frequent low doses) scheduling of anti-cancer drugs combined with anti-angiogenic therapy. The results show that metronomic therapy normalizes the tumor vasculature to improve drug delivery, modulates cancer metabolism, decreases interstitial fluid pressure and decreases cancer cell invasion. Further, we find that combining an anti-cancer drug with anti-angiogenic treatment enhances tumor killing and reduces drug accumulation in normal tissues. We also show that combined anti-angiogenic and anti-cancer drugs can decrease cancer invasiveness and normalize the cancer metabolic microenvironment leading to reduced hypoxia and hypoglycemia. Our model simulations suggest that vessel normalization combined with metronomic cytotoxic therapy has beneficial effects by enhancing tumor killing and limiting normal tissue toxicity.
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spelling pubmed-102498202023-06-09 Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization Nikmaneshi, Mohammad R. Jain, Rakesh K. Munn, Lance L. PLoS Comput Biol Research Article Implementation of effective cancer treatment strategies requires consideration of how the spatiotemporal heterogeneities within the tumor microenvironment (TME) influence tumor progression and treatment response. Here, we developed a multi-scale three-dimensional mathematical model of the TME to simulate tumor growth and angiogenesis and then employed the model to evaluate an array of single and combination therapy approaches. Treatments included maximum tolerated dose or metronomic (i.e., frequent low doses) scheduling of anti-cancer drugs combined with anti-angiogenic therapy. The results show that metronomic therapy normalizes the tumor vasculature to improve drug delivery, modulates cancer metabolism, decreases interstitial fluid pressure and decreases cancer cell invasion. Further, we find that combining an anti-cancer drug with anti-angiogenic treatment enhances tumor killing and reduces drug accumulation in normal tissues. We also show that combined anti-angiogenic and anti-cancer drugs can decrease cancer invasiveness and normalize the cancer metabolic microenvironment leading to reduced hypoxia and hypoglycemia. Our model simulations suggest that vessel normalization combined with metronomic cytotoxic therapy has beneficial effects by enhancing tumor killing and limiting normal tissue toxicity. Public Library of Science 2023-06-08 /pmc/articles/PMC10249820/ /pubmed/37289729 http://dx.doi.org/10.1371/journal.pcbi.1011131 Text en © 2023 Nikmaneshi et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://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
Nikmaneshi, Mohammad R.
Jain, Rakesh K.
Munn, Lance L.
Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization
title Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization
title_full Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization
title_fullStr Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization
title_full_unstemmed Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization
title_short Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization
title_sort computational simulations of tumor growth and treatment response: benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10249820/
https://www.ncbi.nlm.nih.gov/pubmed/37289729
http://dx.doi.org/10.1371/journal.pcbi.1011131
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