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Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.
Mazur, Pawel K; Herner, Alexander; Mello, Stephano S; Wirth, Matthias; Hausmann, Simone; Sánchez-Rivera, Francisco J; Lofgren, Shane M; Kuschma, Timo; Hahn, Stephan A; Vangala, Deepak; Trajkovic-Arsic, Marija; Gupta, Aayush; Heid, Irina; Noël, Peter B; Braren, Rickmer; Erkan, Mert; Kleeff, Jörg; Sipos, Bence; Sayles, Leanne C; Heikenwalder, Mathias; Heßmann, Elisabeth; Ellenrieder, Volker; Esposito, Irene; Jacks, Tyler; Bradner, James E; Khatri, Purvesh; Sweet-Cordero, E Alejandro; Attardi, Laura D; Schmid, Roland M; Schneider, Guenter; Sage, Julien; Siveke, Jens T.
Afiliação
  • Mazur PK; Department of Pediatrics, Stanford University School of Medicine, California, USA.
  • Herner A; Department of Genetics, Stanford University School of Medicine, California, USA.
  • Mello SS; Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Wirth M; Department of Genetics, Stanford University School of Medicine, California, USA.
  • Hausmann S; Department of Radiation Oncology, Stanford University School of Medicine, California, USA.
  • Sánchez-Rivera FJ; Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Lofgren SM; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Kuschma T; David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • Hahn SA; Department of Medicine, Stanford University School of Medicine, California, USA.
  • Vangala D; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA.
  • Trajkovic-Arsic M; Department of Pediatrics, Stanford University School of Medicine, California, USA.
  • Gupta A; Department of Genetics, Stanford University School of Medicine, California, USA.
  • Heid I; Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.
  • Noël PB; Ruhr-University Bochum, Medical Clinic, Knappschaftskrankenhaus, Bochum, Germany.
  • Braren R; Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Erkan M; Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Kleeff J; Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Sipos B; Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Sayles LC; Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Heikenwalder M; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Heßmann E; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Ellenrieder V; Institute of Pathology, University of Tübingen, Tübingen, Germany.
  • Esposito I; Department of Pediatrics, Stanford University School of Medicine, California, USA.
  • Jacks T; Institute of Virology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Bradner JE; Division of Chronic Inflammation and Cancer, German Cancer Research center (DKFZ) Heidelberg, Germany.
  • Khatri P; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.
  • Sweet-Cordero EA; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.
  • Attardi LD; Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Schmid RM; David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • Schneider G; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • Sage J; Department of Medicine, Stanford University School of Medicine, California, USA.
  • Siveke JT; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA.
Nat Med ; 21(10): 1163-71, 2015 Oct.
Article em En | MEDLINE | ID: mdl-26390243
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adenocarcinoma / Proteínas / Carcinoma Ductal Pancreático / Epigênese Genética / Inibidores de Histona Desacetilases Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adenocarcinoma / Proteínas / Carcinoma Ductal Pancreático / Epigênese Genética / Inibidores de Histona Desacetilases Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article