MEK/MELK inhibition and blood-brain barrier deficiencies in atypical teratoid/rhabdoid tumors

  • Neuro Oncol. 2020 Jan 11;22(1):58-69. doi: 10.1093/neuonc/noz151.
Michaël H Meel  1  2 ,  Miriam Guillén Navarro  1 ,  Mark C de Gooijer  3 ,  Dennis S Metselaar  1  2 ,  Piotr Waranecki  1  2 ,  Marjolein Breur  4 ,  Tonny Lagerweij  5 ,  Laurine E Wedekind  5 ,  Jan Koster  6 ,  Marianne D van de Wetering  2  7 ,  Netteke Schouten-van Meeteren  2  7 ,  Eleonora Aronica  8 ,  Olaf van Tellingen  3 ,  Marianna Bugiani  4 ,  Timothy N Phoenix  9 ,  Gertjan J L Kaspers  1  2 ,  Esther Hulleman  1  2
Affiliations
  • 1. Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, Netherlands.
  • 2. Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
  • 3. Division of Pharmacology/Mouse Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 4. Department of Pathology, Amsterdam University Medical Centers, Amsterdam, Netherlands.
  • 5. Department of Neurosurgery, Neuro-oncology Research Group, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, Netherlands.
  • 6. Department of Oncogenomics, Amsterdam University Medical Centers, Amsterdam, Netherlands.
  • 7. Department of Pediatric Oncology, Academic Medical Center, Emma Children's Hospital, Amsterdam, Netherlands.
  • 8. Department of (Neuro) Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
  • 9. Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati/Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
PMID: 31504799 DOI: 10.1093/neuonc/noz151
Abstract

Background: Atypical teratoid/rhabdoid tumors (AT/RT) are rare, but highly aggressive. These entities are of embryonal origin occurring in the central nervous system (CNS) of young children. Molecularly these tumors are driven by a single hallmark mutation, resulting in inactivation of SMARCB1 or SMARCA4. Additionally, activation of the MAPK signaling axis and preclinical antitumor efficacy of its inhibition have been described in AT/RT.

Methods: We established and validated a patient-derived neurosphere culture and xenograft model of sonic Hedgehog (SHH) subtype AT/RT, at diagnosis and relapse from the same patient. We set out to study the vascular phenotype of these tumors to evaluate the integrity of the blood-brain barrier (BBB) in AT/RT. We also used the model to study combined mitogen-activated protein kinase kinase (MEK) and maternal embryonic leucine zipper kinase (MELK) inhibition as a therapeutic strategy for AT/RT.

Results: We found MELK to be highly overexpressed in both patient samples of AT/RT and our primary cultures and xenografts. We identified a potent antitumor efficacy of the MELK Inhibitor OTSSP167, as well as strong synergy with the MEK Inhibitor trametinib, against primary AT/RT neurospheres. Additionally, vascular phenotyping of AT/RT patient material and xenografts revealed significant BBB aberrancies in these tumors. Finally, we show in vivo efficacy of the non-BBB penetrable drugs OTSSP167 and trametinib in AT/RT xenografts, demonstrating the therapeutic implications of the observed BBB deficiencies and validating MEK/MELK inhibition as a potential treatment.

Conclusion: Altogether, we developed a combination treatment strategy for AT/RT based on MEK/MELK inhibition and identify therapeutically exploitable BBB deficiencies in these tumors.

Keywords
atypical teratoid/rhabdoid tumor; blood-brain barrier; maternal embryonic leucine zipper kinase; preclinical therapy development; tumor models.
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