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

Autor: Michael I. Dorrell, Amy L. Rausch, Ryan T. Botts, MaryAnn Alexander, Dawn M. Goral, Daniel J. Elson, Paul Thompson, Stephen A. Bravo, Charisa E. Gillette, Gabriel Villegas, Jacob R. Tremblay, Erik N. Siles, Bridget M. Fortin, Allison L. Hale, Haylie M. Everett, Eric Garcia, Troy L. Kurz, Heidi R. Kast-Woelbern, Connor A. Lowey, Caylor B. Booth, Alec M. Johnson, Michael Wheelock, Carley Coopwood, Sarah Giles, Jessica F. Wada, Jeffrey M. Snowbarger, Roujih Tadros, Jordan A. Silva, Jack C. Rusing, Kaitlyn J. Purington
Rok vydání: 2021
Předmět:
Physiology
Angiogenesis
Tumor Physiology
Cancer Treatment
Angiogenesis Inhibitors
Cardiovascular Physiology
Biochemistry
Chorioallantoic Membrane
Antineoplastic Combined Chemotherapy Protocols
Basic Cancer Research
Tumor Cells
Cultured
Medicine and Health Sciences
Neurological Tumors
Multidisciplinary
Neovascularization
Pathologic
Drug Synergism
Temsirolimus
Bevacizumab
Oncology
Neurology
Tumor Angiogenesis
Medicine
Research Article
medicine.drug
Combination therapy
Blastoma
Science
Malignant Tumors
In vivo
Glioma
medicine
Animals
Humans
Sirolimus
Pharmacology
Drug Screening
business.industry
Biology and Life Sciences
Cancers and Neoplasms
Proteins
Cancer
medicine.disease
In vitro
Rats
Cancer research
Drug Screening Assays
Antitumor
Glioblastoma
business
Chickens
Collagens
Glioblastoma Multiforme
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 16, Iss 6, p e0252233 (2021)
ISSN: 1932-6203
Popis: 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 theex ovochick 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 complexin vivocellular interactions that are difficult to replicatein 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.
Databáze: OpenAIRE
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