BACKGROUND: Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, @entity15200 ( @entity15200 , also termed chromosome region maintenance 1, @entity15200 ) that has demonstrated activity in preclinical models and clinical activity against several solid and hematological @entity5 . PROCEDURES: Selinexor was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0   nM to 10    M 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    M). Selinexor induced significant differences in event-free survival (EFS) distribution in 29 of 38 (76%) of the evaluable @entity5 xenografts and in five of eight (63%) of the evaluable @entity981 xenografts. Objective responses (partial or complete responses, PR/CR) were observed for 4 of 38 @entity5 xenografts including @entity3969 , @entity2946 (n   =   2), and @entity424 models. For the @entity981 panel, two of eight (25%) xenografts achieved either CR or maintained CR. Two responding xenografts had @entity26562 mutations at R465 and two had @entity23423 mutations. Selinexor induced @entity876 , @entity3544 , and cleaved @entity12982 in several @entity5 models. CONCLUSIONS: Selinexor induced regression against several @entity5 and @entity981 xenografts and slowed @entity5 growth in a larger number of models. Pharmacodynamic effects for @entity15200 inhibition were noted. Defining the relationship between selinexor systemic exposures in @entity19 and @entity1 will be important in assessing the clinical relevance of these results. Pediatr @entity5    2015 Wiley Periodicals, Inc.

Pharmacodynamic and genomic markers associated with response to the @entity15200 / XXXX inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program.

@entity1 :: ('9606', 'Species') :: ['humans'] @entity981 :: ('MESH:D054198', 'Disease') :: ['ALL'] @entity424 :: ('MESH:D004806', 'Disease') :: ['ependymoma'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'Blood Cancer', 'cancers', 'solid tumor'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity3544 :: ('644914', 'Gene') :: ['p21'] @entity12982 :: ('142', 'Gene') :: ['PARP'] @entity26562 :: ('55294', 'Gene') :: ['FBXW7'] @entity876 :: ('7157', 'Gene') :: ['p53'] @entity3969 :: ('MESH:D009396', 'Disease') :: ['Wilms tumor'] @entity15200 :: ('7514', 'Gene') :: ['exportin 1', 'XPO1', 'CRM1'] @entity23423 :: ('6597', 'Gene') :: ['SMARCA4'] @entity2946 :: ('MESH:D008527', 'Disease') :: ['medulloblastoma']
@entity15200 :: (7514,Gene) :: ['CRM1']
