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Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG.
Ehteda, Anahid; Simon, Sandy; Franshaw, Laura; Giorgi, Federico M; Liu, Jie; Joshi, Swapna; Rouaen, Jourdin R C; Pang, Chi Nam Ignatius; Pandher, Ruby; Mayoh, Chelsea; Tang, Yujie; Khan, Aaminah; Ung, Caitlin; Tolhurst, Ornella; Kankean, Anne; Hayden, Elisha; Lehmann, Rebecca; Shen, Sylvie; Gopalakrishnan, Anjana; Trebilcock, Peter; Gurova, Katerina; Gudkov, Andrei V; Norris, Murray D; Haber, Michelle; Vittorio, Orazio; Tsoli, Maria; Ziegler, David S.
Afiliación
  • Ehteda A; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Simon S; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Franshaw L; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Giorgi FM; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
  • Liu J; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Joshi S; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Rouaen JRC; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Pang CNI; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
  • Pandher R; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Mayoh C; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
  • Tang Y; State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • Khan A; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Ung C; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Tolhurst O; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Kankean A; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Hayden E; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Lehmann R; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Shen S; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Gopalakrishnan A; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Trebilcock P; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Gurova K; Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Gudkov AV; Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Norris MD; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; Centre for Childhood Cancer Research, University of New South Wales, Sydney, NSW, Australia.
  • Haber M; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Vittorio O; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
  • Tsoli M; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia. Electronic address: mtsoli@ccia.org.au.
  • Ziegler DS; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia; Kid's Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia. Electronic addre
Cell Rep ; 35(2): 108994, 2021 04 13.
Article en En | MEDLINE | ID: mdl-33852836
ABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.
Asunto(s)
Antineoplásicos/farmacología; Neoplasias del Tronco Encefálico/tratamiento farmacológico; Proteínas de Unión al ADN/genética; Glioma Pontino Intrínseco Difuso/tratamiento farmacológico; Epigénesis Genética; Proteínas del Grupo de Alta Movilidad/genética; Histonas/genética; Neuroglía/efectos de los fármacos; Factores de Elongación Transcripcional/genética; Acetilación; Animales; Neoplasias del Tronco Encefálico/genética; Neoplasias del Tronco Encefálico/mortalidad; Neoplasias del Tronco Encefálico/patología; Carbazoles/farmacología; Proteínas de Ciclo Celular/genética; Proteínas de Ciclo Celular/metabolismo; Línea Celular Tumoral; Niño; Cromatina/química; Cromatina/metabolismo; Proteínas de Unión al ADN/metabolismo; Glioma Pontino Intrínseco Difuso/genética; Glioma Pontino Intrínseco Difuso/mortalidad; Glioma Pontino Intrínseco Difuso/patología; Sinergismo Farmacológico; Factor de Transcripción E2F1/genética; Factor de Transcripción E2F1/metabolismo; Epigenoma; Proteínas del Grupo de Alta Movilidad/metabolismo; Histonas/antagonistas & inhibidores; Histonas/metabolismo; Humanos; Metilación; Ratones; Neuroglía/metabolismo; Neuroglía/patología; Panobinostat/farmacología; Cultivo Primario de Células; Proteína de Retinoblastoma/genética; Proteína de Retinoblastoma/metabolismo; Transducción de Señal; Análisis de Supervivencia; Factores de Transcripción/genética; Factores de Transcripción/metabolismo; Factores de Elongación Transcripcional/metabolismo; Proteína p53 Supresora de Tumor/genética; Proteína p53 Supresora de Tumor/metabolismo; Ensayos Antitumor por Modelo de Xenoinjerto
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas del Grupo de Alta Movilidad / Histonas / Neuroglía / Neoplasias del Tronco Encefálico / Factores de Elongación Transcripcional / Epigénesis Genética / Proteínas de Unión al ADN / Glioma Pontino Intrínseco Difuso / Antineoplásicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Rep Año: 2021 Tipo del documento: Article País de afiliación: Australia
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas del Grupo de Alta Movilidad / Histonas / Neuroglía / Neoplasias del Tronco Encefálico / Factores de Elongación Transcripcional / Epigénesis Genética / Proteínas de Unión al ADN / Glioma Pontino Intrínseco Difuso / Antineoplásicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Rep Año: 2021 Tipo del documento: Article País de afiliación: Australia