title: Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma.
abstract: BACKGROUND
  Glioblastoma (GBM) is poorly responsive to current chemotherapy. The nuclear transporter exportin 1 (XPO1, CRM1) is often highly expressed in GBM, which may portend a poor prognosis. Here, we determine the efficacy of novel selective inhibitors of nuclear export (SINE) specific to XPO1 in preclinical models of GBM.
  
  
  METHODS
  Seven patient-derived GBM lines were treated with 3 SINE compounds (KPT-251, KPT-276, and Selinexor) in neurosphere culture conditions. KPT-276 and Selinexor were also evaluated in a murine orthotopic patient-derived xenograft (PDX) model of GBM. Cell cycle effects were assayed by flow cytometry in vitro and immunohistochemistry in vivo. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase 3/7 activity assays.
  
  
  RESULTS
  Treatment of GBM neurosphere cultures with KPT-276, Selinexor, and KPT-251 revealed dose-responsive growth inhibition in all 7 GBM lines [range of half-maximal inhibitory concentration (IC50), 6-354 nM]. In an orthotopic PDX model, treatment with KPT-276 and Selinexor demonstrated pharmacodynamic efficacy, significantly suppressed tumor growth, and prolonged animal survival. Cellular proliferation was not altered with SINE treatment. Instead, induction of apoptosis was apparent both in vitro and in vivo with SINE treatment, without overt evidence of neurotoxicity.
  
  
  CONCLUSIONS
  SINE compounds show preclinical efficacy utilizing in vitro and in vivo models of GBM, with induction of apoptosis as the mechanism of action. Selinexor is now in early clinical trials in solid and hematological malignancies. Based on these preclinical data and excellent brain penetration, we have initiated clinical trials of Selinexor in patients with relapsed GBM.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Adam L
authors.initials: AL
authors.lastname: Green
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Shakti H
authors.initials: SH
authors.lastname: Ramkissoon
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Kristen
authors.initials: K
authors.lastname: Jones
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Perry
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Jessie Hao-Ru
authors.initials: JH
authors.lastname: Hsu
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Lori A
authors.initials: LA
authors.lastname: Ramkissoon
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Cecile L
authors.initials: CL
authors.lastname: Maire
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hubbell-Engler
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: David S
authors.initials: DS
authors.lastname: Knoff
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (A.L.G., J.A.P., J.H.-R.H., B.H.-E.); Division of Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts (A.L.G.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., C.L.M., D.S.K., K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Karyopharm Therapeutics, Natick, Massachusetts (D.M., S.S.); Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts (K.J.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pediatrics, Columbia University Medical Center, New York, New York (A.L.K.).
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
mesh_terms: D000178:Acrylamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D006834:Hydrazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D006834:Hydrazines; D028884:Karyopherins; D010069:Oxadiazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014230:Triazoles; D000097606:Exportin 1 Protein; C000603655:KPT-251; C586831:KPT-276; C585161:selinexor
keywords: SINE; apoptosis; exportin 1; glioblastoma; patient-derived xenograft