STMC-24. NOVEL INHIBITOR OF CDK5 SIGNALING AXIS SUPPRESSES SELF-RENEWAL PROPERTIES OF GBM STEM CELLS AND INDUCES APOPTOSIS

Abstract

Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal and multipotent differentiation. Growth is favored by deregulated stem cell division, which enhances the self-renewing population and diminishes the differentiation program. To uncover mechanisms relevant to deregulated cell division in human glioma stem cells, we first developed a novel adult Drosophila brain tumor model in which brat-RNAi is driven by the neuroblast specific promoter inscuteable. Suppressing Brat in this population led to accumulation of actively proliferating neuroblasts and a lethal brain tumor phenotype. Using adult Drosophila brain tumor, we performed a suppressor screen for kinases and found brain specific dCdk5 partially reverses the tumor phenotype. dCdk5 and its human ortholog CDK5 (79% identity) are different than other CDKs because they do not regulate cell cycle in normal cells, but are critical for neurogenesis and survival of mature neurons. Interestingly, many cancers show overactivation of CDK5 signaling, regulating cell cycle and leading to uncontrolled proliferation. To date, not much is known about the role of CDK5 in glioblastoma GBM) and glioma stem cell self-renewal. Our analysis of TCGA data shows that IDH wt GBM has significantly high level of CDK5 compared to the IDH wt lower grade glioma. Using patient-derived (GBM) neurosphere cultures and in vivo xenograft tumors in mice, we further demonstrated that a novel pharmaceutical suppressor of CDK5 signaling axis was capable of suppressing self-renewal properties and glioma stem cell viability by inducing apoptosis. Together, our results show that the CDK5 signaling pathway is important for glioma stem cell survival and that suppressing CDK5 could be a novel therapeutic approach to eliminate glioma stem cells.