MELK Inhibition in Diffuse Intrinsic Pontine Glioma

Clin Cancer Res. 2018 Nov 15;24(22):5645-5657. doi: 10.1158/1078-0432.CCR-18-0924. Epub 2018 Jul 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Stem Neoplasms / drug therapy
  • Brain Stem Neoplasms / metabolism*
  • Brain Stem Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression
  • Glioma / drug therapy
  • Glioma / metabolism*
  • Glioma / pathology*
  • Humans
  • Mice, Transgenic
  • Neoplasm Staging
  • PPAR gamma / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Tumor Burden
  • Xenograft Model Antitumor Assays


  • PPAR gamma
  • Protein Kinase Inhibitors
  • MELK protein, human
  • Protein Serine-Threonine Kinases