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:	Michael I Dorrell, Heidi R Kast-Woelbern, Ryan T Botts, Stephen A Bravo, Jacob R Tremblay, Sarah Giles, Jessica F Wada, MaryAnn Alexander, Eric Garcia, Gabriel Villegas, Caylor B Booth, Kaitlyn J Purington, Haylie M Everett, Erik N Siles, Michael Wheelock, Jordan A Silva, Bridget M Fortin, Connor A Lowey, Allison L Hale, Troy L Kurz, Jack C Rusing, Dawn M Goral, Paul Thompson, Alec M Johnson, Daniel J Elson, Roujih Tadros, Charisa E Gillette, Carley Coopwood, Amy L Rausch, Jeffrey M Snowbarger
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2bcc474f3f2743d2ae3bcf6edb8e2f29
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spelling	oai:doaj.org-article:2bcc474f3f2743d2ae3bcf6edb8e2f292021-12-02T20:05:22ZA novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis.1932-620310.1371/journal.pone.0252233https://doaj.org/article/2bcc474f3f2743d2ae3bcf6edb8e2f292021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252233https://doaj.org/toc/1932-6203Tumor 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.Michael I DorrellHeidi R Kast-WoelbernRyan T BottsStephen A BravoJacob R TremblaySarah GilesJessica F WadaMaryAnn AlexanderEric GarciaGabriel VillegasCaylor B BoothKaitlyn J PuringtonHaylie M EverettErik N SilesMichael WheelockJordan A SilvaBridget M FortinConnor A LoweyAllison L HaleTroy L KurzJack C RusingDawn M GoralPaul ThompsonAlec M JohnsonDaniel J ElsonRoujih TadrosCharisa E GilletteCarley CoopwoodAmy L RauschJeffrey M SnowbargerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0252233 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael I Dorrell Heidi R Kast-Woelbern Ryan T Botts Stephen A Bravo Jacob R Tremblay Sarah Giles Jessica F Wada MaryAnn Alexander Eric Garcia Gabriel Villegas Caylor B Booth Kaitlyn J Purington Haylie M Everett Erik N Siles Michael Wheelock Jordan A Silva Bridget M Fortin Connor A Lowey Allison L Hale Troy L Kurz Jack C Rusing Dawn M Goral Paul Thompson Alec M Johnson Daniel J Elson Roujih Tadros Charisa E Gillette Carley Coopwood Amy L Rausch Jeffrey M Snowbarger A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis.
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.
format	article
author	Michael I Dorrell Heidi R Kast-Woelbern Ryan T Botts Stephen A Bravo Jacob R Tremblay Sarah Giles Jessica F Wada MaryAnn Alexander Eric Garcia Gabriel Villegas Caylor B Booth Kaitlyn J Purington Haylie M Everett Erik N Siles Michael Wheelock Jordan A Silva Bridget M Fortin Connor A Lowey Allison L Hale Troy L Kurz Jack C Rusing Dawn M Goral Paul Thompson Alec M Johnson Daniel J Elson Roujih Tadros Charisa E Gillette Carley Coopwood Amy L Rausch Jeffrey M Snowbarger
author_facet	Michael I Dorrell Heidi R Kast-Woelbern Ryan T Botts Stephen A Bravo Jacob R Tremblay Sarah Giles Jessica F Wada MaryAnn Alexander Eric Garcia Gabriel Villegas Caylor B Booth Kaitlyn J Purington Haylie M Everett Erik N Siles Michael Wheelock Jordan A Silva Bridget M Fortin Connor A Lowey Allison L Hale Troy L Kurz Jack C Rusing Dawn M Goral Paul Thompson Alec M Johnson Daniel J Elson Roujih Tadros Charisa E Gillette Carley Coopwood Amy L Rausch Jeffrey M Snowbarger
author_sort	Michael I Dorrell
title	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_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_sort	novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/2bcc474f3f2743d2ae3bcf6edb8e2f29
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A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis.

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