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EnglishPediatric 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.
Antonelli, R., Jimenez, C., Riley, M., Servidei, T., Riccardi, R., Soriano, A., Roma, J., Martinez-saez, E., Martini, M., Ruggiero, A., Moreno, L., De Toledo, J. S., Gallego, S., Bove, J., Hooker, J. M., Segura, M. F., CN133, a novel brain-penetrating histone deacetylase inhibitor, hampers tumor growth in patient-derived pediatric posterior fossa ependymoma, <<CANCERS>>, 2020; 12 (7): 1-17. [doi:10.3390/cancers12071922] [http://hdl.handle.net/10807/166131]
| Autori: | ||
| Titolo: | CN133, a novel brain-penetrating histone deacetylase inhibitor, hampers tumor growth in patient-derived pediatric posterior fossa ependymoma | |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.3390/cancers12071922 | |
| Data di pubblicazione: | 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. | |
| Lingua: | Inglese | |
| Rivista: | ||
| Citazione: | Antonelli, R., Jimenez, C., Riley, M., Servidei, T., Riccardi, R., Soriano, A., Roma, J., Martinez-saez, E., Martini, M., Ruggiero, A., Moreno, L., De Toledo, J. S., Gallego, S., Bove, J., Hooker, J. M., Segura, M. F., CN133, a novel brain-penetrating histone deacetylase inhibitor, hampers tumor growth in patient-derived pediatric posterior fossa ependymoma, <<CANCERS>>, 2020; 12 (7): 1-17. [doi:10.3390/cancers12071922] [http://hdl.handle.net/10807/166131] | |
| Appare nelle tipologie: | Articolo in rivista, Nota a sentenza |
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