CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models

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 posteri...

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Detalles Bibliográficos
Autores: Antonelli, Roberta|||0000-0001-6884-7847, Jiménez Jiménez, Carlos|||0000-0001-9219-3492, Riley, Misha, Servidei, Tiziana|||0000-0003-0529-7686, Riccardi, Riccardo, Soriano, Aroa|||0000-0001-9659-1471, Roma, Josep|||0000-0001-7692-6123, Martinez-Saez, Elena|||0000-0001-6004-5364, Martini, Maurizio|||0000-0002-6260-6310, Ruggiero, Antonio|||0000-0002-6052-3511, Moreno Martin Retortillo, Lucas|||0000-0002-0708-1670, Sánchez de Toledo Codina, José|||0000-0002-1034-1920, Gallego, Soledad|||0000-0002-4712-9624, Bové, Jordi|||0000-0002-2529-205X, Hooker, Jacob M., Segura, Miguel F.|||0000-0003-0916-3618
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:252784
Acceso en línea:https://ddd.uab.cat/record/252784
https://dx.doi.org/urn:doi:10.3390/cancers12071922
Access Level:acceso abierto
Palabra clave:Pediatric brain tumors
Posterior fossa ependymoma
Epigenetic therapies
Histone deacetylase inhibitors (HDACi)
Descripción
Sumario: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.

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