Abstract 203: Inhibiting invasion and stemness in glioblastoma by thymosin beta 4 gene silencing: a new therapeutic target

Abstract

Abstract Glioblastoma are incurable primary brain tumors with one of the worst 5-year survival rate among all cancers. Despite multimodality treatment involving neurosurgical intervention, radiation and temozolomide chemotherapy, the median overall survival is in the range of 15-16 months. Four large phase III trials investigating dose-dense temozolomide (RTOG0525) or the addition of the integrin inhitibor cilengitide (CENTRIC) or the addition of vascular endothelial growth factor (VEGF) antibody bevacizumab (RTOG 0828, AVAglio) to the current standard treatment failed to extend this range. Novel therapeutic targets are urgently needed. Thymosin beta 4 (TB4) is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. TB4 gene silencing promotes differentiation of neural progenitor cells whereas TB4 overexpression initiates cortical folding of developing brain hemispheres. Moreover, TB4 is involved in migration invasion and epithelial to mesenchymal transition in other cancer entities, e.g. colon cancer. In the present study, we investigated the role of TB4 in malignant glioma. TB4 expression increased with the grade of malignancy in gliomas and correlated with patient survival. In vitro, TB4 gene silencing decreased migration, invasion, growth and self-renewal, and promoted differentiation and the susceptibility to undergo apoptotic cell death upon nutrient depletion in LNT-229, U87MG and the glioma stem-cell line GS2, respectively. In vivo, survival of nude mice bearing tumors derived from TB4-depleted glioma cells was improved and the tumorigenicity of the GS2 glioma-initiating cell line was diminished. The gene expression pattern in TB4-silenced glioma cells was shifted from the mesenchymal towards the pro-neural gene signature. The clustering of differentially regulated genes involved TGF-beta and p53 signaling networks. Taken together, our data indicate that TB4 may be a novel regulator of malignancy in glioblastoma and therefore a candidate therapeutic target. Citation Format: Hans-Georg Wirsching, Shanmugarajan Krishnan, Ana-Maria Florea, Karl Frei, Niklaus Krayenbühl, Kathy Hasenbach, Guido Reifenberger, Michael Weller, Ghazaleh Tabatabai. Inhibiting invasion and stemness in glioblastoma by thymosin beta 4 gene silencing: a new therapeutic target. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 203. doi:10.1158/1538-7445.AM2014-203