TY - JOUR
T1 - CN133, a novel brain-penetrating histone deacetylase inhibitor, hampers tumor growth in patient-derived pediatric posterior fossa ependymoma
AU - Antonelli, Roberta
AU - Jiménez, Carlos
AU - Riley, Misha
AU - Servidei, Tiziana
AU - Riccardi, Riccardo
AU - Soriano, Aroa
AU - Roma, Josep
AU - Martínez-Saez, Elena
AU - Martini, Maurizio
AU - Ruggiero, Antonio
AU - Moreno, Lucas
AU - de Toledo, Josep Sánchez
AU - Gallego, Soledad
AU - Bové, Jordi
AU - Hooker, Jacob M.
AU - Segura, Miguel F.
N1 - Funding Information:
Funding: This work was funded by Asociación Española Contra el Cáncer-Junta de Barcelona (Grant no.
Funding Information:
AECC/2017/ANTONELLI); Asociación FADAM; Joan Petit foundation; Asociación Pulseras Candela foundation and the #delhospitalalacatedral innitiative led by Xavi Vallés; Instituto de Salud Carlos III (Grant no. CP16/00006, PI17/00564 to M.F Segura; PI15/01937 and PI18/01894 to J. Bové) and Rotary Clubs de Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst y otros de Barcelona y provincia.
Funding Information:
This work was funded by Asociaci?n Espa?ola Contra el C?ncer-Junta de Barcelona (Grant no. AECC/2017/ANTONELLI); Asociaci?n FADAM; Joan Petit foundation; Asociaci?n Pulseras Candela foundation and the #delhospitalalacatedral innitiative led by Xavi Vall?s; Instituto de Salud Carlos III (Grant no. CP16/00006, PI17/00564 to M.F Segura; PI15/01937 and PI18/01894 to J. Bov?) and Rotary Clubs de Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, M?nchen-Blutenburg, Deutschland Gemeindienst y otros de Barcelona y provincia. We thank members of Translational Research in Child and Adolescent Cancer laboratory for their support and the Laboratory Animal Service and Imaging Unit for technical support. We are grateful to Paola Zacchi (University of Trieste, Italy) for critical discussion during manuscript preparation and to Christine O?Hara for text revision.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - Epigenetic therapies
KW - Histone deacetylase inhibitors (HDACi)
KW - Pediatric brain tumors
KW - Posterior fossa ependymoma
UR - http://www.scopus.com/inward/record.url?scp=85088485901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088485901&partnerID=8YFLogxK
U2 - 10.3390/cancers12071922
DO - 10.3390/cancers12071922
M3 - Article
AN - SCOPUS:85088485901
VL - 12
SP - 1
EP - 17
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 7
M1 - 1922
ER -