B-339 AVIL as a Therapeutic Target in GBM: Insights into Cell Death Mechanisms

Abstract Background Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, with no effective cure and a median survival of less than two years despite decades of intensive research. We have identified Advillin (AVIL) as a novel oncogene that is highly overexpressed in GBM. AVIL, an actin-binding protein belonging to the gelsolin/villin family, plays a critical role in actin dynamics, which is essential for its oncogenic functions. Silencing AVIL eliminates GBM cells in culture and significantly suppresses tumor growth in vitro and in vivo. Notably, AVIL expression is highly restricted under normal physiological conditions, being primarily detected during embryonic development and in sensory neurons, making it a promising and selective therapeutic target for GBM. To further explore AVIL’s role in GBM survival, we have identified a novel small molecule, C1, which exhibits high specificity for GBM cells as well as AVIL overexpressing cell both in vitro and in vivo. However, the precise mechanism by which AVIL depletion leads to cell death remains unclear. Methods and Results Using siRNA-mediated AVIL silencing and C1 treatment, we employ biochemical assays, live-cell imaging, and electron microscopy to elucidate the underlying mechanisms. Our findings indicate that AVIL inhibition disrupts actin dynamics and alters cellular homeostasis. Notably, C1 treatment decreases actin remodeling and induces a cell death pathway that is partially rescued by autophagy inhibition. Additionally, cell death inhibitors fail to fully rescue AVIL mediated cell death, suggesting that while autophagy suppression delays cell death, the cells remain committed to dying, with features of multiple cell death pathways Conclusion These results support the hypothesis that AVIL regulates actin dynamics to modulate autophagy and cell death. Targeting AVIL presents a promising therapeutic strategy for GBM by exploiting its selective expression and essential role in tumor survival.