title: Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program.
abstract: BACKGROUND
  Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1, CRM1) that has demonstrated activity in preclinical models and clinical activity against several solid and hematological cancers.
  
  
  METHODS
  Selinexor was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg thrice weekly for 4 weeks.
  
  
  RESULTS
  Selinexor demonstrated cytotoxic activity in vitro, with a median relative IC50 value of 123 nM (range 13.0 nM to >10 μM). Selinexor induced significant differences in event-free survival (EFS) distribution in 29 of 38 (76%) of the evaluable solid tumor xenografts and in five of eight (63%) of the evaluable ALL xenografts. Objective responses (partial or complete responses, PR/CR) were observed for 4 of 38 solid tumor xenografts including Wilms tumor, medulloblastoma (n = 2), and ependymoma models. For the ALL panel, two of eight (25%) xenografts achieved either CR or maintained CR. Two responding xenografts had FBXW7 mutations at R465 and two had SMARCA4 mutations. Selinexor induced p53, p21, and cleaved PARP in several solid tumor models.
  
  
  CONCLUSIONS
  Selinexor induced regression against several solid tumor and ALL xenografts and slowed tumor growth in a larger number of models. Pharmacodynamic effects for XPO1 inhibition were noted. Defining the relationship between selinexor systemic exposures in mice and humans will be important in assessing the clinical relevance of these results.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.affiliation: Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.affiliation: Texas Tech University Health Sciences Center, Lubbock, Texas.
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.affiliation: Texas Tech University Health Sciences Center, Lubbock, Texas.
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.affiliation: The Children's Hospital at Montefiore, Bronx, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.affiliation: A.I. duPont Hospital for Children, Wilmington, Delaware.
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Karyopharm Therapeutics, Newton, Massachusetts.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics, Newton, Massachusetts.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lyalin
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C585161:selinexor
keywords: XPO1 inhibitor; developmental therapeutics; preclinical testing