CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models
Por:
Antonelli, R, Jiménez, C, Riley, M, Servidei, T, Riccardi, R, Soriano, A, Roma, J, Martínez-Saez, E, Martini, M, Ruggiero, A, Moreno, L, Sanchez deToledo J, Gallego, S, Bové, J, Hooker, JM and Segura, MF
Publicada:
1 jul 2020
Resumen:
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.
Filiaciones:
Antonelli, R:
Univ Autonoma Barcelona UAB, Grp Translat Res Child & Adolescent Canc, Vall dHebron Res Inst VHIR, Barcelona 08035, Spain
Jiménez, C:
Univ Autonoma Barcelona UAB, Grp Translat Res Child & Adolescent Canc, Vall dHebron Res Inst VHIR, Barcelona 08035, Spain
Riley, M:
Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA
Harvard Med Sch, Charlestown, MA 02129 USA
Servidei, T:
Fdn Policlin Univ A Gemelli IRCCS, UOC Oncol Pediat, I-00168 Rome, Italy
Riccardi, R:
Fdn Policlin Univ A Gemelli IRCCS, UOC Oncol Pediat, I-00168 Rome, Italy
Soriano, A:
Univ Autonoma Barcelona UAB, Grp Translat Res Child & Adolescent Canc, Vall dHebron Res Inst VHIR, Barcelona 08035, Spain
Roma, J:
Univ Autonoma Barcelona UAB, Grp Translat Res Child & Adolescent Canc, Vall dHebron Res Inst VHIR, Barcelona 08035, Spain
Martínez-Saez, E:
Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Dept Pathol, Barcelona 08035, Spain
Martini, M:
Univ Cattolica Sacro Cuore, Fdn Policlin A Gemelli IRCCS, Dept Pathol, Lgo A Gemelli 8, I-00141 Rome, Italy
Ruggiero, A:
Fdn Policlin Univ A Gemelli IRCCS, UOC Oncol Pediat, I-00168 Rome, Italy
Moreno, L:
Univ Autonoma Barcelona UAB, Grp Translat Res Child & Adolescent Canc, Vall dHebron Res Inst VHIR, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Pediat Oncol & Hematol Dept, Hosp Univ Vall dHebron, Passeig Vall dHebron 119, Barcelona 08035, Spain
Sanchez deToledo J:
Univ Autonoma Barcelona UAB, Grp Translat Res Child & Adolescent Canc, Vall dHebron Res Inst VHIR, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Pediat Oncol & Hematol Dept, Hosp Univ Vall dHebron, Passeig Vall dHebron 119, Barcelona 08035, Spain
Gallego, S:
Univ Autonoma Barcelona UAB, Grp Translat Res Child & Adolescent Canc, Vall dHebron Res Inst VHIR, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Pediat Oncol & Hematol Dept, Hosp Univ Vall dHebron, Passeig Vall dHebron 119, Barcelona 08035, Spain
Bové, J:
Ctr Networked Biomed Res Neurodegenerat Dis CIBER, Vall dHebron Res Inst, Neurodegenerat Dis Res Grp, Barcelona 08035, Spain
Hooker, JM:
Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA
Harvard Med Sch, Charlestown, MA 02129 USA
Segura, MF:
Univ Autonoma Barcelona UAB, Grp Translat Res Child & Adolescent Canc, Vall dHebron Res Inst VHIR, Barcelona 08035, Spain
gold, Green Published
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