CN133, a novel brain-penetrating histone deacetylase inhibitor, hampers tumor growth in patient-derived pediatric posterior fossa ependymoma

Maurizio Martini, Antonio Ruggiero, Riccardo Riccardi, Roberta Antonelli, Carlos Jiménez, Misha Riley, Aroa Soriano, Josep Roma, Elena Martínez-Saez, Lucas Moreno, Josep Sánchez De Toledo, Soledad Gallego, Jordi Bové, Jacob M. Hooker, Miguel F. Segura

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

2 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)1-17
Numero di pagine17
RivistaCancers
Volume12
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • Epigenetic therapies
  • Histone deacetylase inhibitors (HDACi)
  • Pediatric brain tumors
  • Posterior fossa ependymoma

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