AG488 as a therapy against gliomas

// Jadith Ziegler 1, 2 , Anja Bastian 3 , Megan Lerner 4 , Lora Bailey-Downs 3 , Debra Saunders 1 , Nataliya Smith 1 , Jake Sutton 1 , James D. Battiste 5 , Michael A. Ihnat 3 , Aleem Gangjee 6 and Rheal A. Towner 1, 2, 3, 5 1 Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA 2 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 4 Department of Surgery Research Laboratory, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 5 Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 6 Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA Correspondence to: Rheal A. Towner, email: Rheal-Towner@omrf.org Keywords: gliomas, magnetic resonance imaging (MRI), in vivo , anti-cancer therapy, angiogenesis Received: February 13, 2017     Accepted: May 05, 2017     Published: May 30, 2017 ABSTRACT High-grade gliomas such as glioblastomas (GBM) present a deadly prognosis following diagnosis and very few effective treatment options. Here, we investigate if the small molecule AG488 can be an effective therapy against GBM with both anti-angiogenic as well as an anti-microtubule inhibiting modalities, using a human G55 glioma xenograft model in nude mice. From in vitro studies, we report that AG488 incubation reduced cell viability in G55 and HMEC-1 cells more so than TMZ treatment, and AG488 treatment also decreased cell viability in normal astrocytes, but not as much as for G55 cells (p<0.0001). In vivo investigations indicated that AG488 therapy helped reduce tumor volumes (p<0.0001), prolong survival (p<0.01), increase tumor perfusion (p<0.01), and decrease microvessel density (MVD) (p<0.05), compared to untreated mice or mice treated with non-specific IgG, in the G55 xenograft model. Additionally, AG488 did not induce apoptosis in normal mouse brain tissue. Animal survival and tumor volume changes for AG488 were comparable to TMZ or anti-VEGF therapies, however AG488 was found to be more effective in decreasing tumor-related vascularity (perfusion and MVD). AG488 is a potential novel therapy against high-grade gliomas.