{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:02:25Z","timestamp":1792803745000,"version":"4.5.0"},"reference-count":33,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,17]],"date-time":"2022-09-17T00:00:00Z","timestamp":1663372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ChadTough Defeat DIPG Foundation","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}]},{"name":"the SoSo Strong Foundation","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}]},{"name":"the Pediatric Brain Tumor Foundation","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}],"id":[{"id":"https:\/\/ror.org\/052ckfz09","id-type":"ROR","asserted-by":"crossref"}]},{"name":"the Emily Beazley\u2019s Kures for Kids Fund","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}]},{"name":"St. Baldrick\u2019s Foundation","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}],"id":[{"id":"https:\/\/ror.org\/03h1gea69","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NCI K08CA256045 Mentored Clinician Scientist Career Development","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}]},{"name":"NCI U19CA264385 Glioblastoma Therapeutics Network and Cancer Center","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}]},{"name":"NCI P50CA190991 Duke SPORE in Brain Cancer developmental","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}]},{"name":"NCI R35CA197616","award":["P30CA014236"],"award-info":[{"award-number":["P30CA014236"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia\u2013telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre\/loxP recombinase technology and the RCAS\/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.<\/jats:p>","DOI":"10.3390\/cancers14184506","type":"journal-article","created":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T22:12:43Z","timestamp":1663539163000},"page":"4506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma"],"prefix":"10.3390","volume":"14","author":[{"given":"Connor E.","family":"Stewart","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda E.","family":"Guerra-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixia","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerissa T.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5142-0978","authenticated-orcid":false,"given":"Joshua A.","family":"Regal","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debosir","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8060-6026","authenticated-orcid":false,"given":"Patrick","family":"Sansone","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Oldham","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Deland","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4016-8492","authenticated-orcid":false,"given":"Oren J.","family":"Becher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Mt. Sinai Hospital, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Kirsch","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9122-9550","authenticated-orcid":false,"given":"Zachary J.","family":"Reitman","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,17]]},"reference":[{"key":"ref_1","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"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1111\/bpa.12336","article-title":"Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations","volume":"26","author":"Solomon","year":"2015","journal-title":"Brain Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/ng.2995","article-title":"Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas","volume":"46","author":"Zhang","year":"2014","journal-title":"Nat. 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