MEK/MELK inhibition and blood-brain barrier deficiencies in atypical teratoid/rhabdoid tumors.
Animals
Blood-Brain Barrier
/ pathology
Cell Proliferation
/ drug effects
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinase Kinases
/ antagonists & inhibitors
Naphthyridines
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Pyridones
/ pharmacology
Pyrimidinones
/ pharmacology
Rhabdoid Tumor
/ enzymology
Spheroids, Cellular
/ drug effects
Teratoma
/ enzymology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
atypical teratoid/rhabdoid tumor
blood-brain barrier
maternal embryonic leucine zipper kinase
preclinical therapy development
tumor models
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
11 01 2020
11 01 2020
Historique:
pubmed:
11
9
2019
medline:
11
2
2021
entrez:
11
9
2019
Statut:
ppublish
Résumé
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. 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. 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. Altogether, we developed a combination treatment strategy for AT/RT based on MEK/MELK inhibition and identify therapeutically exploitable BBB deficiencies in these tumors.
Sections du résumé
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.
Identifiants
pubmed: 31504799
pii: 5554477
doi: 10.1093/neuonc/noz151
pmc: PMC6954444
doi:
Substances chimiques
1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone
0
Naphthyridines
0
Protein Kinase Inhibitors
0
Pyridones
0
Pyrimidinones
0
trametinib
33E86K87QN
MELK protein, human
EC 2.7.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
58-69Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. For commercial re-use, please contact journals.permissions@oup.com.
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