An effective kinase inhibition strategy for metastatic recurrent childhood medulloblastoma.

Humans Child Mice Animals Adolescent Medulloblastoma / pathology Xenograft Model Antitumor Assays Neoplasm Recurrence, Local / drug therapy Brain Neoplasms / drug therapy Disease Models, Animal Protein Kinase Inhibitors / pharmacology Cerebellar Neoplasms / pathology Cell Line, Tumor
High-throughput screening Kinase inhibitors Recurrent medulloblastoma Spinal metastases

Journal

Journal of neuro-oncology
ISSN: 1573-7373
Titre abrégé: J Neurooncol
Pays: United States
ID NLM: 8309335

Informations de publication

Date de publication:
Jul 2023
Historique:
received: 06 05 2023
accepted: 13 06 2023
medline: 2 8 2023
pubmed: 24 6 2023
entrez: 24 6 2023
Statut: ppublish

Résumé

Medulloblastomas (MBs) constitute the most common malignant brain tumor in children and adolescents. MYC-amplified Group 3 MBs are characterized by disease recurrence, specifically in the leptomeninges, whereby patients with these metastatic tumors have a mortality rate nearing 100%. Despite limited research on such tumors, studies on MB metastases at diagnosis suggest targeting kinases to be beneficial. To identify kinase inhibitors that eradicate cells driving therapy evasion and tumor dissemination, we utilized our established patient-derived xenograft (PDX) mouse-adapted therapy platform that models human MB metastatic recurrences following standard chemoradiotherapy. High-throughput screens of 640 kinase inhibitors were conducted against cells isolated from mouse spines in the PDX model and human fetal neural stem cells to reveal compounds that targeted these treatment-refractory, metastatic cells, whilst sparing healthy cells. Blood-brain barrier permeability assays and additional in vitro experimentation helped select top candidates for in vivo studies. Recurrent Group 3 MB PDX spine cells were therapeutically vulnerable to a selective checkpoint kinase 1 (CHK1) inhibitor and small molecular inhibitor of platelet-derived growth factor receptor beta (PDGFRβ). Inhibitor-treated cells showed a significant reduction in MB stem cell properties associated with treatment failure. Mice also demonstrated survival advantage when treated with a CHK1 inhibitor ex vivo. We identified CHK1 and PDGFRβ inhibitors that effectively target MB cells fueling treatment-refractory metastases. With limited research on effective therapies for Group 3 MB metastatic recurrences, this work highlights promising therapeutic options to treat these aggressive tumors. Additional studies are warranted to investigate these inhibitors' mechanisms and recommended in vivo administration.

Identifiants

DOI: 10.1007/s11060-023-04372-w PMID: 37354357
pubmed: 37354357
doi: 10.1007/s11060-023-04372-w
pii: 10.1007/s11060-023-04372-w
doi:

Substances chimiques

Protein Kinase Inhibitors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

635-645

Subventions

Organisme : CIHR
ID : #MOP-130317
Pays : Canada
Organisme : CIHR
ID : #MOP-130317
Pays : Canada

Informations de copyright

© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

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Auteurs

Ashley A Adile (AA)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
ORCID: 0000-0002-3700-7527

David Bakhshinyan (D)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
ORCID: 0000-0002-1917-7354

Yujin Suk (Y)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
ORCID: 0000-0002-3966-3771

David Uehling (D)

Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, M5G 0A3, Canada.

Mehakpreet Saini (M)

Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, M5G 0A3, Canada.

Ahmed Aman (A)

Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, M5G 0A3, Canada.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
ORCID: 0000-0002-0275-205X

Jakob Magolan (J)

Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
ORCID: 0000-0002-2947-8580

Minomi K Subapanditha (MK)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.

Dillon McKenna (D)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.

Chirayu Chokshi (C)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.

Neil Savage (N)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.

Michelle M Kameda-Smith (MM)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
ORCID: 0000-0003-0904-9946

Chitra Venugopal (C)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.

Sheila K Singh (SK)

Centre for Discovery in Cancer Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. ssingh@mcmaster.ca.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. ssingh@mcmaster.ca.
Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. ssingh@mcmaster.ca.
Human Cancer Stem Cell Biology, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. ssingh@mcmaster.ca.
Neurosurgey, McMaster Children's Hospital, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. ssingh@mcmaster.ca.
ORCID: 0000-0003-1272-5300

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › An effective kinase inhibition strategy for...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › An effective kinase inhibition strategy for...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › An effective kinase inhibition strategy for...
questionsmedicales.fr › Eucaryotes › Animaux › An effective kinase inhibition strategy for...
questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › An effective kinase inhibition strategy for...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Tumeurs neuroectodermiques primitives › Médulloblastome › An effective kinase inhibition strategy for...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › An effective kinase inhibition strategy for...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › An effective kinase inhibition strategy for...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › An effective kinase inhibition strategy for...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › An effective kinase inhibition strategy for...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › An effective kinase inhibition strategy for...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Tumeurs sous-tentorielles › Tumeurs du cervelet › An effective kinase inhibition strategy for...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › An effective kinase inhibition strategy for...