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NIH Public AccessAuthor ManuscriptNat Med. Author manuscript; out there in PMC 2014 Could 01.Published in final edited type as: Nat Med. 2013 November ; 19(11): 1518523. doi:10.1038/nm.3328.NIHPA Author Manuscript NIHPA Author Manuscript NIHPA Author ManuscriptCoordinate activation of Shh and PI3K signaling in PTENdeficient glioblastoma: new therapeutic opportunitiesMariella GruberFilbin1,2,three, Sukriti K. Dabral1,2, Maria F. PazyraMurphy1,two, Shakti Ramkissoon4,five, Andrew L. Kung1,six, Ekaterina Pak1,2, Jarom Chung1,two, Matthew A. Theisen4, Yanping Sun6, Yoko Franchetti7, Yu Sun1,two, David S. Shulman1, Navid Redjal8, Barbara Tabak4, Rameen Beroukhim4, Qi Wang1, Jean Zhao1, Marion Dorsch9, Silvia Buonamici10, Keith L. Ligon4,five, Joseph F. Kelleher10, and Rosalind A. Segal1,2 1Depts of Cancer Biology and Pediatric Oncology, DanaFarber Cancer Institute and Children’s Hospital Boston, Harvard Health-related College, Boston, MA 02115, USA2Dept 3Dept 4Deptof Neurobiology, Harvard Healthcare College, Boston, MA 02115, USA of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austriaof Healthcare Oncology, Center for Molecular Oncologic Pathology, DanaFarber Cancer Institute, Boston, MA 02215, USA5Deptsof Pathology, Children’s Hospital Boston and Brigham and Women’s Hospital, Harvard Health-related School, Boston, MA 02115, USA6Lurie 7DeptFamily Imaging Center, DanaFarber Cancer Institute, Boston, MA 02115, USAof Biostatistics and Computational Biology, DanaFarber Cancer Institute and Harvard School of Public Overall health, Boston, MA 02115, USA8Deptof Neurological Surgery, Massachusetts Basic Hospital, Harvard Medical School, Boston, MA 02114, USA9SanofiAventis, 10NovartisCambridge, MA 02139, USAInstitutes for Biomedical Analysis, Cambridge, MA 02139, USAAbstractIn glioblastoma, PI3kinase (PI3K) signaling is often activated by loss from the tumor suppressor PTEN1.Price of Silver(I) 2,2,2-trifluoroacetate On the other hand, it can be not recognized no matter if inhibiting PI3K represents a selective and productive strategy for therapy.95464-05-4 In stock Here we interrogate substantial databases and locate that Shh signaling is activated in PTENdeficient glioblastoma.PMID:33716140 We demonstrate that Shh and PI3K pathways synergize to market tumor growth and viability in human PTENdeficient glioblastomas. A combination of PI3K and Shh signaling inhibitors not simply suppresses activation of each pathways, but additionally abrogates S6kinase signaling. Accordingly, simultaneously targeting both pathways benefits in mitotic catastrophe and tumor apoptosis, and significantly reduces development of PTENdeficient glioblastomas in vitro and in vivo. The drugs tested right here appear safe in humans; for that reason this combination may well supply new targeted remedy for glioblastoma.Contact: Correspondence and requests for supplies needs to be addressed to [email protected]. Author contributions Manuscript written by MGO, SKD, EP, RAS with input from all authors. MGO, SKD, EP, JC, MFPM, YS executed in vitro research and analyzed in vitro and in vivo studies. ALK, YS, YF, JFK, SB and MD performed in vivo studies. MAT, KLL, SR generated GBM lines, analyzed tumor pathology. DSS, NR initiated these studies. BT, RB analyzed databases. JZ, QW offered shPTEN. Microarray information in Supplementary Figure 4 deposited in NCBI’s Gene Expression Omnibus;.
