{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:09:03Z","timestamp":1792649343715,"version":"4.5.0"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006458","name":"Children\u2019s Hospital of Philadelphia","doi-asserted-by":"publisher","award":["lab startup funds"],"award-info":[{"award-number":["lab startup funds"]}],"id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH2010124"],"award-info":[{"award-number":["W81XWH2010124"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["T32HG009495"],"award-info":[{"award-number":["T32HG009495"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016618","name":"Gilbert Family Foundation","doi-asserted-by":"publisher","award":["722002"],"award-info":[{"award-number":["722002"]}],"id":[{"id":"10.13039\/100016618","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001545","name":"Children\u2019s Tumor Foundation","doi-asserted-by":"publisher","award":["CTF-2022-05-002"],"award-info":[{"award-number":["CTF-2022-05-002"]}],"id":[{"id":"10.13039\/100001545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001445","name":"Alex\u2019s Lemonade Stand Foundation for Childhood Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001445","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["2R25NS065745-06"],"award-info":[{"award-number":["2R25NS065745-06"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Neurofibromatosis Type 1 (NF1) patients develop an array of benign and malignant tumors, of which Malignant Peripheral Nerve Sheath Tumors (MPNST) and High Grade Gliomas (HGG) have a dismal prognosis. About 15\u201320% of individuals with NF1 develop brain tumors and one third of these occur outside of the optic pathway. These non-optic pathway gliomas are more likely to progress to malignancy, especially in adults. Despite their low frequency, high grade gliomas have a disproportional effect on the morbidity of NF1 patients. <jats:italic>In vitro<\/jats:italic> drug combination screens have not been performed on NF1-associated HGG, hindering our ability to develop informed clinical trials. Here we present the first <jats:italic>in vitro<\/jats:italic> drug combination screen (21 compounds alone or in combination with MEK or PI3K inhibitors) on the only human NF1 patient derived HGG cell line available and on three mouse glioma cell lines derived from the NF1-P53 genetically engineered mouse model, which sporadically develop HGG. These mouse glioma cell lines were never exposed to serum, grow as spheres and express markers that are consistent with an Oligodendrocyte Precursor Cell (OPC) lineage origin. Importantly, even though the true cell of origin for HGG remains elusive, they are thought to arise from the OPC lineage. We evaluated drug sensitivities of the three murine glioma cell lines in a 3D spheroid growth assay, which more accurately reflects drug sensitivities <jats:italic>in vivo<\/jats:italic>. Excitingly, we identified six compounds targeting HDACs, BRD4, CHEK1, BMI-1, CDK1\/2\/5\/9, and the proteasome that potently induced cell death in our NF1-associated HGG. Moreover, several of these inhibitors work synergistically with either MEK or PI3K inhibitors. This study forms the basis for further pre-clinical evaluation of promising targets, with an eventual hope to translate these to the clinic.<\/jats:p>","DOI":"10.1371\/journal.pone.0277305","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T18:56:51Z","timestamp":1675364211000},"page":"e0277305","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Identification of therapeutic sensitivities in a spheroid drug combination screen of Neurofibromatosis Type I associated High Grade Gliomas"],"prefix":"10.1371","volume":"18","author":[{"given":"Jacquelyn","family":"Dougherty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyra","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Liou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3308-1620","authenticated-orcid":true,"given":"Katherine","family":"Labella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Moran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Brosius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7492-851X","authenticated-orcid":true,"given":"Thomas","family":"De Raedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"issue":"Pt 6","key":"pone.0277305.ref001","first-page":"1355","article-title":"Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales","volume":"111","author":"SM Huson","year":"1988","journal-title":"Brain"},{"issue":"3","key":"pone.0277305.ref002","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/jid.2014.465","article-title":"Incidence and mortality of neurofibromatosis: a total population study in Finland","volume":"135","author":"E Uusitalo","year":"2015","journal-title":"J Invest Dermatol"},{"issue":"2","key":"pone.0277305.ref003","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/ajmg.a.33139","article-title":"Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service","volume":"152A","author":"DG Evans","year":"2010","journal-title":"Am J Med Genet A"},{"key":"pone.0277305.ref004","doi-asserted-by":"crossref","first-page":"17004","DOI":"10.1038\/nrdp.2017.4","article-title":"Neurofibromatosis type 1","volume":"3","author":"DH Gutmann","year":"2017","journal-title":"Nat Rev Dis 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to target c-Myc","volume":"146","author":"JE Delmore","year":"2011","journal-title":"Cell"},{"key":"pone.0277305.ref034","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41698-019-0106-1","article-title":"Off-target effect of the BMI1 inhibitor PTC596 drives epithelial-mesenchymal transition in glioblastoma multiforme","volume":"4","author":"A Flamier","year":"2020","journal-title":"NPJ Precis Oncol"},{"issue":"1","key":"pone.0277305.ref035","doi-asserted-by":"crossref","first-page":"18489","DOI":"10.1038\/s41598-020-75578-5","article-title":"Dinaciclib, a cyclin-dependent kinase inhibitor, suppresses cholangiocarcinoma growth by targeting CDK2\/5\/9","volume":"10","author":"H Saqub","year":"2020","journal-title":"Sci Rep"}],"container-title":["PLOS 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