Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program

Edward F. Attiyeh, John M. Maris, Richard Lock, C. Patrick Reynolds, Min H. Kang, Hernan Carol, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, Jianrong Wu, Yosef Landesman, Sharon Shacham, Dmitry Lyalin, Raushan T. Kurmasheva, Peter J Houghton, Malcolm A. Smith

Research output: Contribution to journalArticle

9 Citations (Scopus)

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. Procedures: 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. Pediatr Blood Cancer

Original languageEnglish (US)
Pages (from-to)276-286
Number of pages11
JournalPediatric Blood and Cancer
Volume63
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Fingerprint

Heterografts
Chromosomes
Maintenance
Pediatrics
Neoplasms
Ependymoma
Mutation
Medulloblastoma
Cell Nucleus Active Transport
Wilms Tumor
KPT-330
Cytoplasmic and Nuclear Receptors
Inhibitory Concentration 50
Disease-Free Survival
Cell Line
Growth

Keywords

  • developmental therapeutics
  • preclinical testing
  • XPO1 inhibitor

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330) : A report from the pediatric preclinical testing program. / Attiyeh, Edward F.; Maris, John M.; Lock, Richard; Reynolds, C. Patrick; Kang, Min H.; Carol, Hernan; Gorlick, Richard; Kolb, E. Anders; Keir, Stephen T.; Wu, Jianrong; Landesman, Yosef; Shacham, Sharon; Lyalin, Dmitry; Kurmasheva, Raushan T.; Houghton, Peter J; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 63, No. 2, 01.02.2016, p. 276-286.

Research output: Contribution to journalArticle

Attiyeh, EF, Maris, JM, Lock, R, Reynolds, CP, Kang, MH, Carol, H, Gorlick, R, Kolb, EA, Keir, ST, Wu, J, Landesman, Y, Shacham, S, Lyalin, D, Kurmasheva, RT, Houghton, PJ & Smith, MA 2016, 'Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 63, no. 2, pp. 276-286. https://doi.org/10.1002/pbc.25727
Attiyeh, Edward F. ; Maris, John M. ; Lock, Richard ; Reynolds, C. Patrick ; Kang, Min H. ; Carol, Hernan ; Gorlick, Richard ; Kolb, E. Anders ; Keir, Stephen T. ; Wu, Jianrong ; Landesman, Yosef ; Shacham, Sharon ; Lyalin, Dmitry ; Kurmasheva, Raushan T. ; Houghton, Peter J ; Smith, Malcolm A. / Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330) : A report from the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2016 ; Vol. 63, No. 2. pp. 276-286.
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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. Procedures: 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. Pediatr Blood Cancer",
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