VEGF Alpha Research Articles

Investigating Expression Dynamics of miR-21 and miR-10b in Glioblastoma Cells In Vitro: Insights into Responses to Hypoxia and Secretion Mechanisms.

Glioblastoma poses significant challenges in oncology, with bevacizumab showing promise as an antiangiogenic treatment but with limited efficacy. microRNAs (miRNAs) 10b and 21 have emerged as potential biomarkers for bevacizumab response in glioblastoma patients. This study delves into the expression dynamics of miR-21 and miR-10b in response to hypoxia and explores their circulation mechanisms. In vitro experiments exposed glioma cells (A172, U87MG, U251) and human umbilical vein endothelial cells (HUVEC) to hypoxic conditions (1% oxygen) for 24 h, revealing heightened levels of miR-10b and miR-21 in glioblastoma cells. Manipulating miR-10b expression in U87MG, demonstrating a significant decrease in VEGF alpha (VEGFA) following miR-10b overexpression under hypoxic conditions. Size exclusion chromatography illustrated a notable shift towards miR-21 and miR-10b exosomal packaging during hypoxia. A proposed model suggests that effective bevacizumab treatment reduces VEGFA levels, heightening hypoxia and subsequently upregulating miR-21 and miR-10b expression. These miRNAs, released via exosomes, might impact various cellular processes, with miR-10b notably contributing to VEGFA level reduction. However, post-treatment increases in miR-10b and miR-21 could potentially restore cells to normoxic conditions through the downregulation of VEGF. This study highlights the intricate feedback loop involving miR-10b, miR-21, and VEGFA in glioblastoma treatment, underscoring the necessity for personalized therapeutic strategies. Further research should explore clinical implications for personalized glioma treatments.

Abstract A003: Anti-angiogenic activity of the CXCR4 antagonist balixafortide

Abstract Background: Balixafortide is a potent and selective antagonist of the chemokine receptor CXCR4, and is in PhIII for metastatic HER2-negative breast cancer in combination with eribulin (NCT03786094). Clinical proof-of concept of the combination with comparable tolerability to that of eribulin monotherapy was demonstrated in a recent PhI single arm dose-escalation trial (NCT01837095). Balixafortide can inhibit tumor growth through several mechanisms including chemosensitization in combination with chemotherapy (e.g. eribulin), suppression of metastasis, and activation of immune cell response in the tumor microenvironment. In addition, data regarding the co-regulation of the angiogenic factor VEGF and CXCR4 in colorectal cancer (CRC) tissue suggest a possible anti-angiogenic activity of Balixafortide. Methods: VEGF alpha-induced migration of endothelial cells and vascular permeabilization were assessed in vitro. Changes in VEGF alpha levels were determined in CXF260 CRC PDX tumor samples by Nanostring and in CXF260 cells in vitro by qPCR. Results: Balixafortide potently inhibited VEGF alpha-induced migration and permeabilization of an endothelial monolayer in vitro and reduced VEGF alpha levels in both, cultured CXF260 tumor cells in vitro and CXF260 tumors in vivo. Conclusions: Balixafortide modulates angiogenic mechanisms in vitro and in vivo and suggests further investigation of balixafortide in anti-angiogenic therapies. Citation Format: Johann Zimmermann, Daniel Obrecht, Tobias Remus. Anti-angiogenic activity of the CXCR4 antagonist balixafortide [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A003. doi:10.1158/1535-7163.TARG-19-A003