title: BRAF Status in Personalizing Treatment Approaches for Pediatric Gliomas.
abstract: Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low-grade gliomas (PLGGs), and mTOR activation has been documented in the majority of these tumors. We investigated combinations of MEK1/2, BRAFV600Eand mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway.
  
  
  
  We used human glioma lines containing BRAFV600E(adult high-grade: AM-38, DBTRG, PLGG: BT40), or wild-type BRAF (pediatric high-grade: SF188, SF9427, SF8628) and isogenic systems of KIAA1549:BRAF-expressing NIH/3T3 cells and BRAFV600E-expressing murine brain cells. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAFV600E), and AZD6244 (MEK1/2). Proliferation was determined using ATP-based assays. In vivo inhibitor activities were assessed in the BT40 PLGG xenograft model.
  
  
  
  In BRAFV600Ecells, the three possible doublet combinations of AZD6244, everolimus, and PLX4720 exhibited significantly greater effects on cell viability. In BRAFWTcells, everolimus + AZD6244 was superior compared with respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF cells, MEK1/2 inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the BRAFV600Epediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244 + PLX4720 (P < 0.01).
  
  
  
  In BRAFV600Etumors, combination of AZD6244 + PLX4720 is superior to monotherapy and to other combinatorial approaches. In BRAFWTpediatric gliomas, everolimus + AZD6244 is superior to either agent alone. KIAA1549:BRAF-expressing tumors display marked sensitivity to MEK1/2 inhibition. Application of these results to PLGG treatment must be exercised with caution because the dearth of PLGG models necessitated only a single patient-derived PLGG (BT40) in this study. Clin Cancer Res; 22(21); 5312-21. ©2016 AACR.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Olow
authors.affiliation: Brain Tumor Research Center, University of California, San Francisco, Helen-Diller Cancer Diller Cancer Research Center, San Francisco, California.|Department of Neurology, University of California, San Francisco, San Francisco, California.|Department of Pediatrics, University of California, San Francisco, San Francisco, California.|Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Sabine
authors.initials: S
authors.lastname: Mueller
authors.affiliation: Brain Tumor Research Center, University of California, San Francisco, Helen-Diller Cancer Diller Cancer Research Center, San Francisco, California.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neurological Surgery, Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.affiliation: Brain Tumor Research Center, University of California, San Francisco, Helen-Diller Cancer Diller Cancer Research Center, San Francisco, California.
authors.forename: Justin
authors.initials: J
authors.lastname: Meyerowitz
authors.affiliation: Brain Tumor Research Center, University of California, San Francisco, Helen-Diller Cancer Diller Cancer Research Center, San Francisco, California.|Department of Neurology, University of California, San Francisco, San Francisco, California.|Department of Pediatrics, University of California, San Francisco, San Francisco, California.
authors.forename: William
authors.initials: W
authors.lastname: Weiss
authors.affiliation: Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Resnick
authors.affiliation: Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Waanders
authors.affiliation: Department of Radiotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Lukas J A
authors.initials: LJ
authors.lastname: Stalpers
authors.affiliation: Brain Tumor Research Center, University of California, San Francisco, Helen-Diller Cancer Diller Cancer Research Center, San Francisco, California.|Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.affiliation: Brain Tumor Research Center, University of California, San Francisco, Helen-Diller Cancer Diller Cancer Research Center, San Francisco, California.|Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Nalin
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Neurological Surgery, Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Petritsch
authors.affiliation: Brain Tumor Research Center, University of California, San Francisco, Helen-Diller Cancer Diller Cancer Research Center, San Francisco, California. dhaas-kogan@lroc.harvard.edu.|Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.|Department of Radiation Oncology, Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2