| Title: | CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models |
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| Author: | Antonelli, Roberta; Jiménez, Carlos; Riley, Misha; Servidei, Tiziana; Riccardi, Riccardo; Soriano, Aroa; Roma, Josep; Martinez-Saez, Elena; Martini, Maurizio; Ruggiero, Antonio; Moreno, Lucas; Sánchez de Toledo Codin, Josep; Gallego, Soledad; Bové, Jordi; Hooker, Jacob M.; Segura, Miguel F.; Universitat Autònoma de Barcelona |
| 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 |
| Subject(s): | -Pediatric brain tumors -Posterior fossa ependymoma -Epigenetic therapies -Histone deacetylase inhibitors (HDACi) |
| Rights: | open access
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| Document type: | Article |
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| Uri: | https://ddd.uab.cat/record/252784 |
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