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A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis

Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angi...

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Autores principales: Dorrell, Michael I., Kast-Woelbern, Heidi R., Botts, Ryan T., Bravo, Stephen A., Tremblay, Jacob R., Giles, Sarah, Wada, Jessica F., Alexander, MaryAnn, Garcia, Eric, Villegas, Gabriel, Booth, Caylor B., Purington, Kaitlyn J., Everett, Haylie M., Siles, Erik N., Wheelock, Michael, Silva, Jordan A., Fortin, Bridget M., Lowey, Connor A., Hale, Allison L., Kurz, Troy L., Rusing, Jack C., Goral, Dawn M., Thompson, Paul, Johnson, Alec M., Elson, Daniel J., Tadros, Roujih, Gillette, Charisa E., Coopwood, Carley, Rausch, Amy L., Snowbarger, Jeffrey M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172048/
https://www.ncbi.nlm.nih.gov/pubmed/34077449
http://dx.doi.org/10.1371/journal.pone.0252233
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author Dorrell, Michael I.
Kast-Woelbern, Heidi R.
Botts, Ryan T.
Bravo, Stephen A.
Tremblay, Jacob R.
Giles, Sarah
Wada, Jessica F.
Alexander, MaryAnn
Garcia, Eric
Villegas, Gabriel
Booth, Caylor B.
Purington, Kaitlyn J.
Everett, Haylie M.
Siles, Erik N.
Wheelock, Michael
Silva, Jordan A.
Fortin, Bridget M.
Lowey, Connor A.
Hale, Allison L.
Kurz, Troy L.
Rusing, Jack C.
Goral, Dawn M.
Thompson, Paul
Johnson, Alec M.
Elson, Daniel J.
Tadros, Roujih
Gillette, Charisa E.
Coopwood, Carley
Rausch, Amy L.
Snowbarger, Jeffrey M.
author_facet Dorrell, Michael I.
Kast-Woelbern, Heidi R.
Botts, Ryan T.
Bravo, Stephen A.
Tremblay, Jacob R.
Giles, Sarah
Wada, Jessica F.
Alexander, MaryAnn
Garcia, Eric
Villegas, Gabriel
Booth, Caylor B.
Purington, Kaitlyn J.
Everett, Haylie M.
Siles, Erik N.
Wheelock, Michael
Silva, Jordan A.
Fortin, Bridget M.
Lowey, Connor A.
Hale, Allison L.
Kurz, Troy L.
Rusing, Jack C.
Goral, Dawn M.
Thompson, Paul
Johnson, Alec M.
Elson, Daniel J.
Tadros, Roujih
Gillette, Charisa E.
Coopwood, Carley
Rausch, Amy L.
Snowbarger, Jeffrey M.
author_sort Dorrell, Michael I.
collection PubMed
description Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.
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spelling pubmed-81720482021-06-14 A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis Dorrell, Michael I. Kast-Woelbern, Heidi R. Botts, Ryan T. Bravo, Stephen A. Tremblay, Jacob R. Giles, Sarah Wada, Jessica F. Alexander, MaryAnn Garcia, Eric Villegas, Gabriel Booth, Caylor B. Purington, Kaitlyn J. Everett, Haylie M. Siles, Erik N. Wheelock, Michael Silva, Jordan A. Fortin, Bridget M. Lowey, Connor A. Hale, Allison L. Kurz, Troy L. Rusing, Jack C. Goral, Dawn M. Thompson, Paul Johnson, Alec M. Elson, Daniel J. Tadros, Roujih Gillette, Charisa E. Coopwood, Carley Rausch, Amy L. Snowbarger, Jeffrey M. PLoS One Research Article Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients. Public Library of Science 2021-06-02 /pmc/articles/PMC8172048/ /pubmed/34077449 http://dx.doi.org/10.1371/journal.pone.0252233 Text en © 2021 Dorrell 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
Dorrell, Michael I.
Kast-Woelbern, Heidi R.
Botts, Ryan T.
Bravo, Stephen A.
Tremblay, Jacob R.
Giles, Sarah
Wada, Jessica F.
Alexander, MaryAnn
Garcia, Eric
Villegas, Gabriel
Booth, Caylor B.
Purington, Kaitlyn J.
Everett, Haylie M.
Siles, Erik N.
Wheelock, Michael
Silva, Jordan A.
Fortin, Bridget M.
Lowey, Connor A.
Hale, Allison L.
Kurz, Troy L.
Rusing, Jack C.
Goral, Dawn M.
Thompson, Paul
Johnson, Alec M.
Elson, Daniel J.
Tadros, Roujih
Gillette, Charisa E.
Coopwood, Carley
Rausch, Amy L.
Snowbarger, Jeffrey M.
A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis
title A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis
title_full A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis
title_fullStr A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis
title_full_unstemmed A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis
title_short A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis
title_sort novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172048/
https://www.ncbi.nlm.nih.gov/pubmed/34077449
http://dx.doi.org/10.1371/journal.pone.0252233
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