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

作者：Michael Ian Dorrell, Heidi R. Kast-Woelbern, Ryan T. Botts, Stephen Bravo, Jacob R. Tremblay, Sarah Giles, Jessica F. Wada, MaryAnn Alexander, Eric Alejandro García, 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 I. Thompson, Alec M. Johnson, Daniel J. Elson, Roujih Tadros, Charisa E. Gillette, Carley Coopwood, Amy L. Rausch, Jeffrey M. Snowbarger · 发表于：PLoS ONE · 年份：2021 · DOI：10.1371/journal.pone.0252233 · 被引用次数：7 · 研究领域：Glioma Diagnosis and Treatment、Angiogenesis and VEGF in Cancer、Cancer Mechanisms and Therapy

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 re...