cranial brain tumor xenograft growth . Low levels of cAMP have been correlated with malignant brain tumors for many years, but the mechanisms that control these abnormal cAMP levels and their cancer relevant targets are often undefined or remain poorly understood. The cyclic AMP pathway is integral to the regulation of numerous cellular processes including growth and differentiation. While the bulk of cAMP signaling is transmitted by just two mediators, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19672638 protein kinase A and exchange protein activated by cAMP, exquisite specificity in cAMP signaling is achieved through subcellular localization and activation. A critical component of this specification is the establishment of defined intracellular pools of differing cAMP levels as a result of highly localized and regulated cAMP degradation through PDEs. Humans have 11 families of PDEs, three of which are cAMP specific, and each of these families can have multiple gene homologs throughout the genome, and each of these genes can have multiple splicing isoforms. The canonical PDE structure includes a common catalytic domain, an amino terminal subcellular localization motif and regulatory kinase sites and protein-protein interacting domains. Consequently, PDE expression and activation result in the generation of highly specific gradients of intracellular cAMP and the formation of multiprotein signaling complexes that carry out localized functions. This process has been most extensively illustrated for the PDE4 family of cAMP-specific PDEs. While we PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/1967325 have yet to define how PDE7B promotes GBM tumorigenecity, there are some likely mechanisms. Cyclic AMP is a recently established regulator of neural stem cell proliferation, differentiation, and survival, and it is known that endothelial cells in the PVN support GBM CSCs. Therefore the induction of PDE7B expression in tumor cells localized to the perivascular space may function to promote CSC function. The detection of 
a modest, but significant, increase in stemness, as measured by our in vitro limiting dilution assay, in both G144 and U87 cells 7 PDE7B in the GBM Perivascular Niche overexpressing wild type PDE7B is consistent with this hypothesis. This would also be in line with our observation that PDE7B WT intracranial tumors showed signs of increased invasion and aggressiveness compared to the PDE7B H217Q tumors. The increase in blood vessel density in wild type tumors also suggests that tumor cell PDE7B might function as part of a positive feedback loop for promoting angiogenesis. Finally, the effect of PDE7B on outcome in GBM and its ability to drive intracranial tumor growth in the U87 model suggests that inhibition of PDE7B should be evaluated as a novel therapeutic target for GBM. We previously demonstrated that targeted inhibition of an alternate cAMP-specific phosphodiesterase, PDE4, had significant anti-brain tumor activity, when tested in a spontaneous model of low-grade glioma and in intracranial xenograft models of GBM and medulloblastoma . Together with the current findings, these results provide a strong rationale for cAMP elevation in the treatment of brain tumors. While there have not been any studies of specific PDE7B PBTZ 169 web inhibitors in the context of cancer treatment, there has been work done evaluating PDE7B inhibition for the treatment of autoimmune disorders. Therefore future work should focus on taking specific inhibitors of PDE7B from the autoimmune studies and 8 PDE7B in the GBM Perivascular Niche 9 PDE7B in the GBM Perivascul