期刊
CANCERS
卷 12, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/cancers12071922
关键词
pediatric brain tumors; posterior fossa ependymoma; epigenetic therapies; histone deacetylase inhibitors (HDACi)
类别
资金
- Asociacion Espanola Contra el Cancer-Junta de Barcelona [AECC/2017/ANTONELLI]
- Asociacion FADAM
- Joan Petit foundation
- Asociacion Pulseras Candela foundation
- delhospitalalacatedral innitiative
- Instituto de Salud Carlos III [CP16/00006, PI17/00564, PI15/01937, PI18/01894]
- Rotary Clubs de Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, Munchen-Blutenburg, Deutschland Gemeindienst y otros de Barcelona y provincia
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.
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