1. CN133, a novel brain-penetrating histone deacetylase inhibitor, hampers tumor growth in patient-derived pediatric posterior fossa ependymoma
- Author
-
Antonelli, R., Jimenez, C., Riley, M., Servidei, T., Riccardi, Riccardo, Soriano, A., Roma, J., Martinez-Saez, E., Martini, Maurizio, Ruggiero, Antonio, Moreno, L., de Toledo, J. S., Gallego, S., Bove, J., Hooker, J. M., Segura, M. F., Riccardi R. (ORCID:0000-0001-7515-6622), Martini M. (ORCID:0000-0002-6260-6310), Ruggiero A. (ORCID:0000-0002-6052-3511), Antonelli, R., Jimenez, C., Riley, M., Servidei, T., Riccardi, Riccardo, Soriano, A., Roma, J., Martinez-Saez, E., Martini, Maurizio, Ruggiero, Antonio, Moreno, L., de Toledo, J. S., Gallego, S., Bove, J., Hooker, J. M., Segura, M. F., Riccardi R. (ORCID:0000-0001-7515-6622), Martini M. (ORCID:0000-0002-6260-6310), and Ruggiero A. (ORCID:0000-0002-6052-3511)
- 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.
- Published
- 2020