Abstract 3899: ROCK inhibitor as a differentiation-inducing agent to target glioma stem cells

Abstract

Abstract Only 3% of patients diagnosed each year with Glioblastoma Multiforme (GBM) survive longer than 5 years, making GBM one of the most lethal forms of human cancer. It has been proposed that GBMs are driven by a rare subset of tumor cells referred to as cancer stem cells (CSCs), which have the ability to resist conventional radio- and chemotherapy and initiate disease recurrence. Thus, the development of novel and effective therapeutic strategies targeting CSCs is required and should significantly improve the dismal prognosis for patients with GBM. A possible viable strategy to effectively target glioma stem cells (GSCs) is the use of bone morphogenetic proteins (BMPs) as differentiation inducers. Our results suggest that Rho-associated protein kinase (ROCK) could work as a pharmacological negative regulator of BMPs. Our preliminary data indicate that: i) Fasudil, a ROCK1 inhibitor, induces BMP2 and BMP4 expression both in vitro and in vivo in different human-derived glioma xenograft models; ii) Fasudil-induced BMPs can increase the expression of differentiation markers and decrease stemness in these glioma models; iii) temozolomide, a chemotherapeutic agent, converts glioma cells to a GSC phenotype, while Fasudil blocks this interconversion; iv) co-administration of Fasudil with temozolomide inhibits the invasive characteristics of GBM in an orthotropic glioma xenograft model; and v) the analysis of BMP expression in human-derived GBM samples from the Repository of Molecular Brain Neoplasia Database (REMBRABDT) reveals that patients with higher BMP2 expression survived four times longer than those with low or intermediate BMP2 expression (p<0.001). Based on this, we propose that, by blocking ROCK signaling with the FDA approved pharmacological inhibitor Fasudil, one can modulate BMP expression in human-derived gliomas. Fasudil, therefore, may redirect cellular signals regulating GSCs' stemness, fate, and initiate their differentiation. Such an agent will allow us to develop a more effective anti-glioma therapy through its combination with other conventional anti-cancer drugs. Citation Format: Brenda Auffinger, Alex L. Tobias, Yu Han, Maciej S. Lesniak, Atique U. Ahmed. ROCK inhibitor as a differentiation-inducing agent to target glioma stem cells. [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 3899. doi:10.1158/1538-7445.AM2014-3899