title: MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma.
abstract: Glioblastoma multiforme remains the deadliest malignant brain tumor, with glioma stem cells (GSC) contributing to treatment resistance and tumor recurrence. We have identified MAPK-interacting kinases (MNK) as potential targets for the GSC population in glioblastoma multiforme. Isoform-level subtyping using The Cancer Genome Atlas revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal glioblastoma multiforme as compared with other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44, and coexpression of MKNK1 and CD44 predicts poor survival in glioblastoma multiforme. In established and patient-derived cell lines, pharmacologic MNK inhibition using LY2801653 (merestinib) inhibited phosphorylation of the eukaryotic translation initiation factor 4E, a crucial effector for MNK-induced mRNA translation in cancer cells and a marker of transformation. Importantly, merestinib inhibited growth of GSCs grown as neurospheres as determined by extreme limiting dilution analysis. When the effects of merestinib were assessed in vivo using an intracranial xenograft mouse model, improved overall survival was observed in merestinib-treated mice. Taken together, these data provide strong preclinical evidence that pharmacologic MNK inhibition targets mesenchymal glioblastoma multiforme and its GSC population.
  
  
  
  These findings raise the possibility of MNK inhibition as a viable therapeutic approach to target the mesenchymal subtype of glioblastoma multiforme. Mol Cancer Res; 14(10); 984-93. ©2016 AACR.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Bell
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Eckerdt
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Kristen
authors.initials: K
authors.lastname: Alley
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Magnusson
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Hridi
authors.initials: H
authors.lastname: Hussain
authors.affiliation: Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ahmet Dirim
authors.initials: AD
authors.lastname: Arslan
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Division of Hematology/Oncology/Stem Cell Transplantation, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Jessica
authors.initials: J
authors.lastname: Clymer
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Angel A
authors.initials: AA
authors.lastname: Alvarez
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Division of Hematology/Oncology/Stem Cell Transplantation, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois. l-platanias@northwestern.edu.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors; D007191:Indazoles / Q000008:administration & dosage* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D009536:Niacinamide; C586252:merestinib; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases