MELK Inhibition in Diffuse Intrinsic Pontine Glioma
Por:
Meel MH, de Gooijer MC, Guillén Navarro M, Waranecki P, Breur M, Buil L, Wedekind LE, Twisk JWR, Koster J, Hashizume R, Raabe EH, Carcaboso AM, Bugiani M, van Tellingen O, van Vuurden DG, Kaspers GJL and Hulleman E
Publicada:
15 nov 2018
Ahead of Print:
30 jul 2018
Resumen:
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 PPAR gamma,
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-PPAR gamma
signaling axis as a putative therapeutic target in this disease. (C)
2018 AACR.
Filiaciones:
Meel MH:
Pediatric Oncology, VU University Medical Center
de Gooijer MC:
Division of Pharmacology, Netherlands Cancer Institute
Breur M:
Pathology, VU University Medical Center
Buil L:
Department of Clinical Chemistry, Netherlands Cancer Institute
Wedekind LE:
Pediatric Oncology/Hematology, VU University Medical Center
Twisk JWR:
Epidemiology and Biostatistics, VU University Medical Center
Koster J:
Department of Oncogenomics, Amsterdam UMC, University of Amsterdam
Hashizume R:
Neurological surgery, Biochemistry and Molecular Genetics, Northwestern University
Raabe EH:
Division of Pediatric Oncology, Johns Hopkins Hospital
Carcaboso AM:
Hospital Sant Joan de Déu Barcelona
Bugiani M:
Pathology, VU University Medical Center
van Tellingen O:
Division of Pharmacology / MCC, Netherlands Cancer Institute
van Vuurden DG:
Pediatric Oncology, Neuro-oncology Research Group, VU University Medical Center, Cancer Center Amsterdam
Kaspers GJL:
Pediatrics, Pediatric Hematology and Oncology, VU University Medical Center
Hulleman E:
Pediatric Oncology, VU University Medical Center-Cancer Centrer Amsterdam
Open Access
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