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: Adam L Green, Shakti H Ramkissoon, Dilara McCauley, Kristen Jones, Jennifer A Perry, Jessie Hao-Ru Hsu, Lori A Ramkissoon, Cecile L Maire, Benjamin Hubbell-Engler, David S Knoff, Sharon Shacham, Keith L Ligon, Andrew L Kung
• Journal: Neuro-oncology (Neuro Oncol) Vol. 17 Issue 5 Pg. 697-707 (May 2015) ISSN: 1523-5866 [Electronic] England
• PMID: 25366336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Acrylamides
• Antineoplastic Agents
• Hydrazines
• KPT-251
• KPT-276
• Karyopherins
• Oxadiazoles
• Receptors, Cytoplasmic and Nuclear
• Thiazoles
• Triazoles
• exportin 1 protein
• selinexor

Topics

• Acrylamides (pharmacokinetics, pharmacology, therapeutic use)
• Active Transport, Cell Nucleus (drug effects)
• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy)
• Cell Cycle Checkpoints (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Glioblastoma (drug therapy)
• Humans
• Hydrazines (pharmacokinetics, pharmacology, therapeutic use)
• Karyopherins (antagonists & inhibitors, metabolism)
• Macaca fascicularis
• Male
• Mice
• Oxadiazoles (pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, metabolism)
• Thiazoles (pharmacokinetics, pharmacology, therapeutic use)
• Treatment Outcome
• Triazoles (pharmacokinetics, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays