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Characterization of druggable targets in this disease remains a longstanding goal, as no pharmacological agents have proven efficacy in this malignancy. We recently identified the menin inhibitor, MI-2, as exhibiting potent antitumor activity in preclinical models of DIPG. Here, we show that MI-2 exerts its activity in glioma largely independent of its ability to target the epigenetic regulator menin, but instead by disrupting cholesterol homeostasis through direct inhibition of the cholesterol biosynthesis enzyme, lanosterol synthase, revealing this metabolic enzyme as an actionable vulnerability in glioma and implicating cholesterol homeostasis as an attractive pathway to target in malignant gliomas.<\/jats:p>","DOI":"10.1073\/pnas.1820989116","type":"journal-article","created":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T02:55:15Z","timestamp":1553828115000},"page":"7957-7962","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":62,"title":["Target identification reveals lanosterol synthase as a vulnerability in glioma"],"prefix":"10.1073","volume":"116","author":[{"given":"Richard E.","family":"Phillips","sequence":"first","affiliation":[{"name":"Department of Neurology and Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065;"},{"name":"Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan C.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonne M.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Yamasaki","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, 305-8566 Tsukuba, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yadira M.","family":"Soto-Feliciano","sequence":"additional","affiliation":[{"name":"Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Funato","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupu","family":"Liang","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Science, The Rockefeller University, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Garcia-Bermudez","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshi","family":"Wang","sequence":"additional","affiliation":[{"name":"Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Yamasaki","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, 305-8566 Tsukuba, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey G.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kivan\u00e7","family":"Birsoy","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviane","family":"Tabar","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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