CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models
Antonelli, Roberta (Hospital Universitari Vall d'Hebron)
Jiménez Jiménez, Carlos (Vall d'Hebron Institut de Recerca (VHIR))
Riley, Misha (Massachusetts General Hospital (Boston))
Servidei, Tiziana (Fondazione Policlinico Universitario "A. Gemelli" (Roma, Itàlia))
Riccardi, Riccardo (Fondazione Policlinico Universitario "A. Gemelli" (Roma, Itàlia))
Soriano, Aroa (Vall d'Hebron Institut de Recerca (VHIR))
Roma, Josep (Vall d'Hebron Institut de Recerca (VHIR))
Martinez-Saez, Elena (Vall d'Hebron Institut de Recerca (VHIR))
Martini, Maurizio (Catholic University of Sacred Heart)
Ruggiero, Antonio (Fondazione Policlinico Universitario "A. Gemelli" (Roma, Itàlia))
Moreno Martin Retortillo, Lucas (Vall d'Hebron Institut d'Oncologia)
Sánchez de Toledo Codin, Josep (Vall d'Hebron Institut d'Oncologia)
Gallego, Soledad (Vall d'Hebron Institut d'Oncologia)
Bové, Jordi (Vall d'Hebron Institut de Recerca (VHIR))
Hooker, Jacob M. (Massachusetts General Hospital (Boston))
Segura, Miguel F. (Vall d'Hebron Institut de Recerca (VHIR))
Universitat Autònoma de Barcelona

Data:	2020
Resum:	Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa A (PF-EPN-A) and EPN posterior fossa B (PF-EPN-B). Patients with PF-EPN-A have poor outcome and are in demand of new therapies. In general, PF-EPN-A tumors show a balanced chromosome copy number profile and have no recurrent somatic nucleotide variants. However, these tumors present abundant epigenetic deregulations, thereby suggesting that epigenetic therapies could provide new opportunities for PF-EPN-A patients. In vitro epigenetic drug screening of 11 compounds showed that histone deacetylase inhibitors (HDACi) had the highest anti-proliferative activity in two PF-EPN-A patient-derived cell lines. Further screening of 5 new brain-penetrating HDACi showed that CN133 induced apoptosis in vitro, reduced tumor growth in vivo and significantly extended the survival of mice with orthotopically-implanted EPN tumors by modulation of the unfolded protein response, PI3K/Akt/mTOR signaling, and apoptotic pathways among others. In summary, our results provide solid preclinical evidence for the use of CN133 as a new therapeutic agent against PF-EPN-A tumors.
Ajuts:	Instituto de Salud Carlos III CP16/00006 Instituto de Salud Carlos III PI17/00564 Ministerio de Economía y Competitividad PI15/01937 Instituto de Salud Carlos III I18/01894
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Pediatric brain tumors ; Posterior fossa ependymoma ; Epigenetic therapies ; Histone deacetylase inhibitors (HDACi)
Publicat a:	Cancers, Vol. 12 (july 2020) , ISSN 2072-6694

DOI: 10.3390/cancers12071922
PMID: 32708733

17 p, 3.9 MB

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