Abstract 1941: GSK3 signaling is critical to glioma stem cell growth and survival

Abstract

Abstract GSK3 is an attractive therapeutic target in cancer, known for its role in regulating proliferation, differentiation, metabolism, and apoptosis. Previous studies demonstrate the effectiveness of GSK3 inhibition on established glioma cell lines and patient-derived glioma stem cell lines in vitro and in vivo. In glioma cell lines, GSK3 inhibition induces apoptosis through c-MYC activation, mitochondrial destabilization, and reduction of NF-κB activity. We have characterized a novel set of GSK3 inhibitors for their ability to inhibit glycogen synthase phosphorylation, reduce levels of XIAP, and induce cell death in cancer cells. However, it is uncertain if this mechanism is functional with respect to cancer stem cells and glioma tumor subtype. The need to investigate the mechanistic effects of GSK3 in cancer stem cells is important given their malignancy, innate resistance to therapy, and tumorigenicity. Moreover, the intracellular signaling and transcription networks may differ in glioma stem cells, particularly among cells with different subtypes. We have recently demonstrated that cancer stem cells isolated from glioma patients can be segregated into either a proneural or mesenchymal subtype based on their gene expression pattern. The oncogenic activity of genes like c-MYC in glioma stem cells and differences between glioma stem cell subtypes, such as NF-κB activation, raises questions as to whether GSK3 inhibition will be effective against both subtypes and if their effects utilize distinct mechanisms of inhibition. In this study, we examine the effects of two established and two novel GSK3 inhibitors on glioma stem cells with respect to tumor subtype and investigate their mechanisms of action. Our in vitro data shows that GSK3 inhibition significantly reduces growth and causes cell death in both proneural and mesenchymal glioma stem cells. Using a glioma stem cell xenograft model, we test the effectiveness of GSK3 inhibition as a single agent and in conjunction with clinically-approved chemotherapeutic agents. The characterization of cancer stem cell inhibitors and their effectiveness in different tumor subtypes has significant clinical implications. Our work supports the therapeutic potential of novel GSK3 inhibitors for the treatment of malignant gliomas. Note: This abstract was not presented at the meeting. Citation Format: Angel Alvarez, Andrey Ugolkov, Irina Gaisina, Alan P. Kozikowski, Kaushal Joshi, Sunghak Kim, Ichiro Nakano, Jeffrey J. Raizer, Andrew P. Mazar, Bo Hu, Shi-Yuan Cheng. GSK3 signaling is critical to glioma stem cell growth and survival. [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 1941. doi:10.1158/1538-7445.AM2014-1941