Abstract
Purpose: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor, for which no effective therapeutic options currently exist. We here determined the potential of inhibition of the maternal embryonic leucine zipper kinase (MELK) for the treatment of DIPG.Experimental Design: We evaluated the antitumor efficacy of the small-molecule MELK inhibitor OTSSP167 in vitro in patient-derived DIPG cultures, and identified the mechanism of action of MELK inhibition in DIPG by RNA sequencing of treated cells. In addition, we determined the blood-brain barrier (BBB) penetration of OTSSP167 and evaluated its translational potential by treating mice bearing patient-derived DIPG xenografts.Results: This study shows that MELK is highly expressed in DIPG cells, both in patient samples and in relevant in vitro and in vivo models, and that treatment with OTSSP167 strongly decreases proliferation of patient-derived DIPG cultures. Inhibition of MELK in DIPG cells functions through reducing inhibitory phosphorylation of PPARγ, resulting in an increase in nuclear translocation and consequent transcriptional activity. Brain pharmacokinetic analyses show that OTSSP167 is a strong substrate for both MDR1 and BCRP, limiting its BBB penetration. Nonetheless, treatment of Mdr1a/b;Bcrp1 knockout mice carrying patient-derived DIPG xenografts with OTSSP167 decreased tumor growth, induced remissions, and resulted in improved survival.Conclusions: We show a strong preclinical effect of the kinase inhibitor OTSSP167 in the treatment of DIPG and identify the MELK-PPARγ signaling axis as a putative therapeutic target in this disease. Clin Cancer Res; 24(22); 5645-57. ©2018 AACR.
Highlights
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor carrying a dismal prognosis, which remained unchanged over the past decades despite majorNote: Supplementary data for this article are available at Clinical Cancer Research Online.Ó2018 American Association for Cancer Research.advances in the understanding of the molecular biology of this disease over the past years [1]
This study shows that maternal embryonic leucine zipper kinase (MELK) is highly expressed in DIPG cells, both in patient samples and in relevant in vitro and in vivo models, and that treatment with OTSSP167 strongly decreases proliferation of patient-derived DIPG cultures
We show a strong preclinical effect of the kinase inhibitor OTSSP167 in the treatment of DIPG and identify the MELK–PPARg signaling axis as a putative therapeutic target in this disease
Summary
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor carrying a dismal prognosis, which remained unchanged over the past decades despite majorNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2018 American Association for Cancer Research.advances in the understanding of the molecular biology of this disease over the past years [1]. Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor carrying a dismal prognosis, which remained unchanged over the past decades despite major. As in adult high-grade glioma (HGG) and many other cancers, DIPG cells carry mutations in DNA damage repair genes and genes involved in signal transduction pathways, as well as amplifications in receptor tyrosine kinases (RTK) such as EGFR and PDGFRA [2,3,4]. Recent international collaborations have uncovered several unique oncogenic mutations in this disease in the genes encoding Histone 3 [5, 6] and ACVR1 [7,8,9]. The new World Health Organization classification of brain tumors reclassifies DIPG and related tumors as diffuse midline gliomas carrying histone H3 mutations [10]. Current efforts to develop a therapy for this devastating disease focus mainly on reversing the malignant phenotype and altered epigenetic landscape caused by these mutations [11, 12]
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