{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T07:20:58Z","timestamp":1790493658209,"version":"4.1.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T00:00:00Z","timestamp":1554249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"DKTK research program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive pediatric brain tumors that are characterized by a recurrent mutation (K27M) within the histone H3 encoding genes H3F3A and HIST1H3A\/B\/C. These mutations have been shown to induce a global reduction in the repressive histone modification H3K27me3, which together with widespread changes in DNA methylation patterns results in an extensive transcriptional reprogramming hampering the identification of single therapeutic targets based on a molecular rationale.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We applied a large-scale gene knockdown approach using a pooled short hairpin (sh)RNA library in combination with next-generation sequencing in order to identify DIPG-specific vulnerabilities. The therapeutic potential of specific inhibitors of candidate targets was validated in a secondary drug screen.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We identified fibroblast growth factor receptor (FGFR) signaling and the serine\/threonine protein phosphatase 2A (PP2A) as top depleted hits in patient-derived DIPG cell cultures and validated their lethal potential by FGF ligand depletion and genetic knockdown of the PP2A structural subunit PPP2R1A. Further, pharmacological inhibition of FGFR and PP2A signaling through ponatinib and LB-100 treatment, respectively, exhibited strong tumor-specific anti-proliferative and apoptotic activity in cultured DIPG cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings suggest FGFR and PP2A signaling as potential new therapeutic targets for the treatment of DIPGs.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noz057","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T20:23:49Z","timestamp":1553545429000},"page":"867-877","source":"Crossref","is-referenced-by-count":34,"title":["DECIPHER pooled shRNA library screen identifies PP2A and FGFR signaling as potential therapeutic targets for diffuse intrinsic pontine gliomas"],"prefix":"10.1093","volume":"21","author":[{"given":"Kathrin","family":"Schramm","sequence":"first","affiliation":[{"name":"Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Iskar","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"Statz","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"J\u00e4ger","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurooncology, DKFZ, and Hopp Children\u2019s Cancer Center Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Haag","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurooncology, DKFZ, and Hopp Children\u2019s Cancer Center Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miko\u0142aj","family":"S\u0142abicki","sequence":"additional","affiliation":[{"name":"Molecular Therapy in Hematology and Oncology, Department of Translational Oncology, National Center for Tumor Diseases and DKFZ, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan M","family":"Pfister","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurooncology, DKFZ, and Hopp Children\u2019s Cancer Center Heidelberg, Heidelberg, Germany"},{"name":"German Cancer Consortium (DKTK), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Zapatka","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Gronych","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T W","family":"Jones","sequence":"additional","affiliation":[{"name":"Pediatric Glioma Research Group, Hopp Children\u2019s Cancer Center Heidelberg and DKFZ, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lichter","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"name":"German Cancer Consortium (DKTK), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,4,3]]},"reference":[{"issue":"4","key":"2019071105355156100_CIT0001","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.ccell.2017.08.017","article-title":"Integrated molecular meta-analysis of 1000 pediatric high-grade and diffuse intrinsic pontine glioma","volume":"32","author":"Mackay","year":"2017","journal-title":"Cancer Cell."},{"issue":"3","key":"2019071105355156100_CIT0002","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1470-2045(06)70615-5","article-title":"Diffuse brainstem glioma in children: critical review of clinical trials","volume":"7","author":"Hargrave","year":"2006","journal-title":"Lancet Oncol."},{"issue":"3","key":"2019071105355156100_CIT0003","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/ng.1102","article-title":"Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas","volume":"44","author":"Wu","year":"2012","journal-title":"Nat Genet."},{"issue":"5","key":"2019071105355156100_CIT0004","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.ccr.2013.10.006","article-title":"Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas","volume":"24","author":"Bender","year":"2013","journal-title":"Cancer Cell."},{"issue":"9","key":"2019071105355156100_CIT0005","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1101\/gad.217778.113","article-title":"The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression","volume":"27","author":"Chan","year":"2013","journal-title":"Genes Dev."},{"issue":"6134","key":"2019071105355156100_CIT0006","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1126\/science.1232245","article-title":"Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma","volume":"340","author":"Lewis","year":"2013","journal-title":"Science."},{"issue":"5","key":"2019071105355156100_CIT0007","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/ng.2936","article-title":"Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations","volume":"46","author":"Buczkowicz","year":"2014","journal-title":"Nat Genet."},{"issue":"30","key":"2019071105355156100_CIT0008","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.1200\/JCO.2011.35.5677","article-title":"Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma","volume":"29","author":"Paugh","year":"2011","journal-title":"J Clin Oncol."},{"issue":"4","key":"2019071105355156100_CIT0009","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/pbc.24060","article-title":"Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma","volume":"58","author":"Grill","year":"2012","journal-title":"Pediatr Blood Cancer."},{"issue":"5","key":"2019071105355156100_CIT0010","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/ng.2938","article-title":"The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma","volume":"46","author":"Wu","year":"2014","journal-title":"Nat Genet."},{"issue":"1","key":"2019071105355156100_CIT0011","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ctrv.2011.06.007","article-title":"Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology","volume":"38","author":"Jansen","year":"2012","journal-title":"Cancer Treat Rev."},{"issue":"8","key":"2019071105355156100_CIT0012","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/neuonc\/nox021","article-title":"Diffuse intrinsic pontine gliomas\u2014current management and new biologic insights. Is there a glimmer of hope?","volume":"19","author":"Cohen","year":"2017","journal-title":"Neuro Oncol."},{"issue":"7","key":"2019071105355156100_CIT0013","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/nm.3217","article-title":"BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1","volume":"19","author":"T\u00f6njes","year":"2013","journal-title":"Nat Med."},{"issue":"121","key":"2019071105355156100_CIT0014","doi-asserted-by":"crossref","DOI":"10.3791\/55360","article-title":"A protocol for rapid post-mortem cell culture of diffuse intrinsic pontine glioma (DIPG)","author":"Lin","year":"2017","journal-title":"J Vis Exp"},{"issue":"4","key":"2019071105355156100_CIT0015","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ccr.2012.08.024","article-title":"Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma","volume":"22","author":"Sturm","year":"2012","journal-title":"Cancer Cell."},{"issue":"1","key":"2019071105355156100_CIT0016","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.canlet.2013.02.036","article-title":"Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer","volume":"335","author":"Seshacharyulu","year":"2013","journal-title":"Cancer Lett."},{"issue":"W1","key":"2019071105355156100_CIT0017","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: a comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"issue":"11","key":"2019071105355156100_CIT0018","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1158\/1535-7163.MCT-15-0282","article-title":"Poly-ADP-ribose polymerase as a therapeutic target in pediatric diffuse intrinsic pontine glioma and pediatric high-grade astrocytoma","volume":"14","author":"Chornenkyy","year":"2015","journal-title":"Mol Cancer Ther."},{"issue":"10","key":"2019071105355156100_CIT0019","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N Engl J Med."},{"issue":"4","key":"2019071105355156100_CIT0020","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1093\/neuonc\/noq205","article-title":"Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children\u2019s Oncology Group","volume":"13","author":"Cohen","year":"2011","journal-title":"Neuro Oncol."},{"issue":"13","key":"2019071105355156100_CIT0021","doi-asserted-by":"crossref","first-page":"5506","DOI":"10.1158\/0008-5472.CAN-05-0626","article-title":"Isolation and in vitro propagation of tumorigenic breast cancer cells with stem\/progenitor cell properties","volume":"65","author":"Ponti","year":"2005","journal-title":"Cancer Res."},{"issue":"12","key":"2019071105355156100_CIT0022","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1016\/j.febslet.2006.01.095","article-title":"Fibroblast growth factor signaling in embryonic and cancer stem cells","volume":"580","author":"Dvorak","year":"2006","journal-title":"FEBS Lett."},{"issue":"1","key":"2019071105355156100_CIT0023","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2013.12.003","article-title":"The role of basic fibroblast growth factor in glioblastoma multiforme and glioblastoma stem cells and in their in vitro culture","volume":"346","author":"Haley","year":"2014","journal-title":"Cancer Lett."},{"issue":"7","key":"2019071105355156100_CIT0024","first-page":"263","article-title":"Passaging human neural stem cells","author":"Marchenko","year":"2007","journal-title":"J Vis Exp."},{"issue":"3","key":"2019071105355156100_CIT0025","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s11060-009-9885-5","article-title":"Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling","volume":"94","author":"Loilome","year":"2009","journal-title":"J Neurooncol."},{"key":"2019071105355156100_CIT0026","first-page":"2013","article-title":"The effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, against human U87 malignant glioblastoma cells","volume":"7","author":"Zhang","year":"2014","journal-title":"Onco Targets Ther."},{"issue":"1","key":"2019071105355156100_CIT0027","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s12032-010-9445-z","article-title":"Adenovirus-mediated transfer of siRNA against basic fibroblast growth factor mRNA enhances the sensitivity of glioblastoma cells to chemotherapy","volume":"28","author":"Feng","year":"2011","journal-title":"Med Oncol."},{"key":"2019071105355156100_CIT0028","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1042\/bj3110017","article-title":"Serine\/threonine protein phosphatases","volume":"311","author":"Wera","year":"1995","journal-title":"Biochem J."},{"issue":"28","key":"2019071105355156100_CIT0029","doi-asserted-by":"crossref","first-page":"11697","DOI":"10.1073\/pnas.0905930106","article-title":"Inhibition of serine\/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms","volume":"106","author":"Lu","year":"2009","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"2","key":"2019071105355156100_CIT0030","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3171\/2009.11.JNS091272","article-title":"The effect of a PP2A inhibitor on the nuclear receptor corepressor pathway in glioma","volume":"113","author":"Lu","year":"2010","journal-title":"J Neurosurg."},{"issue":"7","key":"2019071105355156100_CIT0031","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1158\/1535-7163.MCT-14-0614","article-title":"Protein phosphatase 2A inhibition with LB100 enhances radiation-induced mitotic catastrophe and tumor growth delay in glioblastoma","volume":"14","author":"Gordon","year":"2015","journal-title":"Mol Cancer Ther."},{"issue":"3","key":"2019071105355156100_CIT0032","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The fibroblast growth factor signaling pathway","volume":"4","author":"Ornitz","year":"2015","journal-title":"Wiley Interdiscip Rev Dev Biol."},{"issue":"37","key":"2019071105355156100_CIT0033","doi-asserted-by":"crossref","first-page":"27178","DOI":"10.1074\/jbc.M601248200","article-title":"N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding","volume":"281","author":"Duchesne","year":"2006","journal-title":"J Biol Chem."},{"issue":"12","key":"2019071105355156100_CIT0034","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1002\/jcp.24649","article-title":"Isoforms of receptors of fibroblast growth factors","volume":"229","author":"Gong","year":"2014","journal-title":"J Cell Physiol."},{"issue":"16","key":"2019071105355156100_CIT0035","doi-asserted-by":"crossref","first-page":"4422","DOI":"10.1158\/1078-0432.CCR-13-0788","article-title":"Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C\/CDK1 and homologous recombination repair","volume":"19","author":"Wei","year":"2013","journal-title":"Clin Cancer Res."},{"issue":"1","key":"2019071105355156100_CIT0036","doi-asserted-by":"crossref","first-page":"2894","DOI":"10.1038\/s41598-017-03058-4","article-title":"PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation","volume":"7","author":"Hu","year":"2017","journal-title":"Sci Rep."},{"issue":"1","key":"2019071105355156100_CIT0037","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1582-4934.2005.tb00337.x","article-title":"The activation of Akt\/PKB signaling pathway and cell survival","volume":"9","author":"Song","year":"2005","journal-title":"J Cell Mol Med."},{"issue":"5","key":"2019071105355156100_CIT0038","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.molcel.2004.07.015","article-title":"Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells","volume":"15","author":"van Vugt","year":"2004","journal-title":"Mol Cell."},{"key":"2019071105355156100_CIT0039","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0065-230X(05)94002-5","article-title":"Activation of AKT kinases in cancer: implications for therapeutic targeting","volume":"94","author":"Bellacosa","year":"2005","journal-title":"Adv Cancer Res."},{"issue":"2","key":"2019071105355156100_CIT0040","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/sj.onc.1208272","article-title":"Polo-like kinases (Plks) and cancer","volume":"24","author":"Takai","year":"2005","journal-title":"Oncogene."},{"key":"2019071105355156100_CIT0041","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1747-1028-4-4","article-title":"The balance of polo-like kinase 1 in tumorigenesis","volume":"4","author":"Lu","year":"2009","journal-title":"Cell Div."},{"issue":"48","key":"2019071105355156100_CIT0042","doi-asserted-by":"crossref","first-page":"19011","DOI":"10.1073\/pnas.0706696104","article-title":"Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner","volume":"104","author":"Andrabi","year":"2007","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"6","key":"2019071105355156100_CIT0043","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1080\/15384047.2015.1040961","article-title":"LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential","volume":"16","author":"Hong","year":"2015","journal-title":"Cancer Biol Ther."}],"container-title":["Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/neuro-oncology\/advance-article-pdf\/doi\/10.1093\/neuonc\/noz057\/28534073\/noz057.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/21\/7\/867\/28926210\/noz057.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,7,11]],"date-time":"2019-07-11T09:37:37Z","timestamp":1562837857000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article\/21\/7\/867\/5426974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,3]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4,3]]},"published-print":{"date-parts":[[2019,7,11]]}},"URL":"https:\/\/doi.org\/10.1093\/neuonc\/noz057","relation":{},"ISSN":["1522-8517","1523-5866"],"issn-type":[{"value":"1522-8517","type":"print"},{"value":"1523-5866","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,7]]},"published":{"date-parts":[[2019,4,3]]}}}