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Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy.
Chen, Jingwei; Nelson, Christopher; Wong, Matthew; Tee, Andrew E; Liu, Pei Y; La, Ting; Fletcher, Jamie I; Kamili, Alvin; Mayoh, Chelsea; Bartenhagen, Christoph; Trahair, Toby N; Xu, Ning; Jayatilleke, Nisitha; Wong, Marie; Peng, Hui; Atmadibrata, Bernard; Cheung, Belamy B; Lan, Qing; Bryan, Tracy M; Mestdagh, Pieter; Vandesompele, Jo; Combaret, Valerie; Boeva, Valentina; Wang, Jenny Y; Janoueix-Lerosey, Isabelle; Cowley, Mark J; MacKenzie, Karen L; Dolnikov, Alla; Li, Jinyan; Polly, Patsie; Marshall, Glenn M; Reddel, Roger R; Norris, Murray D; Haber, Michelle; Fischer, Matthias; Zhang, Xu D; Pickett, Hilda A; Liu, Tao.
Afiliação
  • Chen J; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Nelson C; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Wong M; Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • Tee AE; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Liu PY; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • La T; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Fletcher JI; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Kamili A; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Mayoh C; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Bartenhagen C; School of Medicine and Public Health, Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, Australia.
  • Trahair TN; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Xu N; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Jayatilleke N; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Wong M; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Peng H; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Atmadibrata B; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Cheung BB; Department of Experimental Pediatric Oncology, Medical Faculty, University Hospital, University of Cologne, Cologne, Germany.
  • Lan Q; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
  • Bryan TM; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Mestdagh P; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Vandesompele J; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Combaret V; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Boeva V; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Wang JY; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Janoueix-Lerosey I; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Cowley MJ; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • MacKenzie KL; Advanced Analytics Institute, University of Technology Sydney, Ultimo, Australia.
  • Dolnikov A; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Li J; Children's Cancer Institute, Randwick, Sydney, Australia.
  • Polly P; School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
  • Marshall GM; Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
  • Reddel RR; Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • Norris MD; Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
  • Haber M; Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
  • Fischer M; Centre Léon-Bérard, Laboratoire de Recherche Translationnelle, Lyon, France.
  • Zhang XD; ETH Zürich, Department of Computer Science, Institute for Machine Learning, Swiss Institute of Bioinformaticsics (SIB), Zurich, Switzerland.
  • Pickett HA; Institut Cochin, Inserm U1016, CNRS UMR 8104, Université Paris Descartes UMR-S1016, Paris, France.
  • Liu T; Children's Cancer Institute, Randwick, Sydney, Australia.
Clin Cancer Res ; 27(5): 1438-1451, 2021 03 01.
Article em En | MEDLINE | ID: mdl-33310889
ABSTRACT

PURPOSE:

TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. EXPERIMENTAL

DESIGN:

Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice.

RESULTS:

The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression.

CONCLUSIONS:

OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Fatores de Transcrição / Rearranjo Gênico / Proteínas de Ciclo Celular / Telomerase / Terapia de Alvo Molecular / Compostos Heterocíclicos com 3 Anéis / Acetanilidas / Neuroblastoma Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Clin Cancer Res Assunto da revista: NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Fatores de Transcrição / Rearranjo Gênico / Proteínas de Ciclo Celular / Telomerase / Terapia de Alvo Molecular / Compostos Heterocíclicos com 3 Anéis / Acetanilidas / Neuroblastoma Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Clin Cancer Res Assunto da revista: NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália