MeLK inhibition in diffuse intrinsic pontine glioma

Michael H. Meel, Mark C. De Gooijer, Miriam Guillen Navarro, Piotr Waranecki, Marjolein Breur, Levi C.M. Buil, Laurine E. Wedekind, Jos W.R. Twisk, Jan Koster, Rintaro Hashizume, Eric Raabe, Angel Montero Carcaboso, Marianna Bugiani, Olaf Van Tellingen, Dannis G. Van Vuurden, Gertjan J.L. Kaspers, Esther Hulleman

Research output: Contribution to journalArticle

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 PPARg, 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–PPARg signaling axis as a putative thera-

peutic target in this disease.

Original languageEnglish (US)
Pages (from-to)5645-5657
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number22
DOIs
StatePublished - Nov 15 2018

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Glioma
Leucine Zippers
Phosphotransferases
Mothers
Heterografts
RNA Sequence Analysis
Therapeutics
Knockout Mice
Brain Neoplasms
1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone
Research Design
Pharmacokinetics
Phosphorylation
Pediatrics
Survival
Brain
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Meel, M. H., De Gooijer, M. C., Navarro, M. G., Waranecki, P., Breur, M., Buil, L. C. M., ... Hulleman, E. (2018). MeLK inhibition in diffuse intrinsic pontine glioma. Clinical Cancer Research, 24(22), 5645-5657. https://doi.org/10.1158/1078-0432.CCR-18-0924

MeLK inhibition in diffuse intrinsic pontine glioma. / Meel, Michael H.; De Gooijer, Mark C.; Navarro, Miriam Guillen; Waranecki, Piotr; Breur, Marjolein; Buil, Levi C.M.; Wedekind, Laurine E.; Twisk, Jos W.R.; Koster, Jan; Hashizume, Rintaro; Raabe, Eric; Carcaboso, Angel Montero; Bugiani, Marianna; Van Tellingen, Olaf; Van Vuurden, Dannis G.; Kaspers, Gertjan J.L.; Hulleman, Esther.

In: Clinical Cancer Research, Vol. 24, No. 22, 15.11.2018, p. 5645-5657.

Research output: Contribution to journalArticle

Meel, MH, De Gooijer, MC, Navarro, MG, Waranecki, P, Breur, M, Buil, LCM, Wedekind, LE, Twisk, JWR, Koster, J, Hashizume, R, Raabe, E, Carcaboso, AM, Bugiani, M, Van Tellingen, O, Van Vuurden, DG, Kaspers, GJL & Hulleman, E 2018, 'MeLK inhibition in diffuse intrinsic pontine glioma', Clinical Cancer Research, vol. 24, no. 22, pp. 5645-5657. https://doi.org/10.1158/1078-0432.CCR-18-0924
Meel MH, De Gooijer MC, Navarro MG, Waranecki P, Breur M, Buil LCM et al. MeLK inhibition in diffuse intrinsic pontine glioma. Clinical Cancer Research. 2018 Nov 15;24(22):5645-5657. https://doi.org/10.1158/1078-0432.CCR-18-0924
Meel, Michael H. ; De Gooijer, Mark C. ; Navarro, Miriam Guillen ; Waranecki, Piotr ; Breur, Marjolein ; Buil, Levi C.M. ; Wedekind, Laurine E. ; Twisk, Jos W.R. ; Koster, Jan ; Hashizume, Rintaro ; Raabe, Eric ; Carcaboso, Angel Montero ; Bugiani, Marianna ; Van Tellingen, Olaf ; Van Vuurden, Dannis G. ; Kaspers, Gertjan J.L. ; Hulleman, Esther. / MeLK inhibition in diffuse intrinsic pontine glioma. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 22. pp. 5645-5657.
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T1 - MeLK inhibition in diffuse intrinsic pontine glioma

AU - Meel, Michael H.

AU - De Gooijer, Mark C.

AU - Navarro, Miriam Guillen

AU - Waranecki, Piotr

AU - Breur, Marjolein

AU - Buil, Levi C.M.

AU - Wedekind, Laurine E.

AU - Twisk, Jos W.R.

AU - Koster, Jan

AU - Hashizume, Rintaro

AU - Raabe, Eric

AU - Carcaboso, Angel Montero

AU - Bugiani, Marianna

AU - Van Tellingen, Olaf

AU - Van Vuurden, Dannis G.

AU - Kaspers, Gertjan J.L.

AU - Hulleman, Esther

PY - 2018/11/15

Y1 - 2018/11/15

N2 - 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 PPARg, 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–PPARg signaling axis as a putative thera-peutic target in this disease.

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