Home > Articles > Published articles > CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models |
Date: | 2020 |
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. |
Grants: | 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 |
Rights: | 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. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | Pediatric brain tumors ; Posterior fossa ependymoma ; Epigenetic therapies ; Histone deacetylase inhibitors (HDACi) |
Published in: | Cancers, Vol. 12 (july 2020) , ISSN 2072-6694 |
17 p, 3.9 MB |