We observed that inhibition of RAS signaling in glioblastoma tumors induced by expression of activated RAS and AKT resulted in cell death by apoptosis, indicating the importance of this pathway in glioblastoma servicing within this context. As cAMP suppression is necessary for CXCL12 induced development responses in astrocytes and gliomas, we observed no effect of CXCL12 on wild sort astrocyte growth. In contrast, loss of Nf1 expression was connected to an MEK dependent raise in the inactive phosphorylated type of GRK2 and also a near complete loss of CXCL12 induced, GRK2 mediated CXCR4 phosphorylation. The reduction of CXCR4 phosphorylation in Nf1 deficient astrocytes correlated with sustained suppression of intracel lular cAMP amounts and elevated astrocyte growth. Together, these stud ies produce the very first evidence of the novel form of ligand dependent glioma development regulation in NF1 and indicate that genetic alterations in tumor cells can transform usual homeostatic microenvironmental signals into potent tumor development stimuli.
The identification of cAMP suppression being a development stimulus in NF1 associated gliomas supports the evaluation of cAMP elevating agents, for instance phosphodiesterase inhibitors, while in the deal with ment of patients with NF1 linked gliomas. CB 36. Evaluation OF SIGNALING CASCADES DRIVING GLIOBLASTOMA Servicing Todd A. Whitwam, Matthew W. VanBrocklin, selleck LDE225 and Sheri L. Holmen, Van Andel Research Institute, Grand Rapids, MI, USA The bad efficacy of latest therapies helps make glioblastoma multiforme NVPTAE684 tumors perfect candidates for molecularly targeted therapies. Current advances in molecular biology and proteomics have produced it achievable to iden tify characteristic molecular profiles of GBM, and many genetic altera tions have been identified, but it stays unclear which of those gene prod ucts is needed for tumor maintenance and progression.
In human GBM, signaling through the phosphatidylinositol 3 kinase /AKT and RAS/ mitogen activated protein kinase pathways is thought to originate from abnormally activated receptor tyrosine kinases, which include the epidermal growth component receptor along with the platelet derived growth aspect receptor. The reduction of phosphatase

and tensin homolog deleted on chromosome 10 expression also results in elevated AKT signaling. RAS is activated in almost all cases of GBM1, and AKT is activated in 70% of GBM tumors. Once these kinases are active, they signal many downstream pathways, including multiple survival and cell death signaling cascades. Understanding which of those signaling cascades is required for tumor progression and upkeep has been a major chal lenge in glioma oncology. To determine the signaling cascades that drive glioblastoma maintenance, we used pharmacologic inhibitors to target these pathways in human glioblastoma cell lines and assessed the conse quences of target inhibition on tumor free survival using a mouse model of human GBM based on the avian RCAS/TVA system.