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Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination.
Ham, Jungoh; Costa, Carlotta; Sano, Renata; Lochmann, Timothy L; Sennott, Erin M; Patel, Neha U; Dastur, Anahita; Gomez-Caraballo, Maria; Krytska, Kateryna; Hata, Aaron N; Floros, Konstantinos V; Hughes, Mark T; Jakubik, Charles T; Heisey, Daniel A R; Ferrell, Justin T; Bristol, Molly L; March, Ryan J; Yates, Craig; Hicks, Mark A; Nakajima, Wataru; Gowda, Madhu; Windle, Brad E; Dozmorov, Mikhail G; Garnett, Mathew J; McDermott, Ultan; Harada, Hisashi; Taylor, Shirley M; Morgan, Iain M; Benes, Cyril H; Engelman, Jeffrey A; Mossé, Yael P; Faber, Anthony C.
Afiliação
  • Ham J; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Costa C; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Sano R; Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Lochmann TL; Department of Microbiology and Immunology, Massey Cancer Center, Richmond, VA 23298, USA.
  • Sennott EM; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Patel NU; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Dastur A; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Gomez-Caraballo M; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Krytska K; Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Hata AN; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Floros KV; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Hughes MT; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Jakubik CT; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Heisey DA; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Ferrell JT; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Bristol ML; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • March RJ; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Yates C; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Hicks MA; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Nakajima W; Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki 211-8533, Japan.
  • Gowda M; Department of Pediatrics, Children's Hospital of Richmond, VCU, Richmond, VA 23298, USA.
  • Windle BE; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Dozmorov MG; Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Garnett MJ; Cancer Genome Project, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
  • McDermott U; Cancer Genome Project, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
  • Harada H; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Taylor SM; Department of Microbiology and Immunology, Massey Cancer Center, Richmond, VA 23298, USA.
  • Morgan IM; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
  • Benes CH; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Engelman JA; Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Mossé YP; Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Faber AC; Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA. Electronic address: acfaber@vcu.edu.
Cancer Cell ; 29(2): 159-72, 2016 Feb 08.
Article em En | MEDLINE | ID: mdl-26859456
ABSTRACT
Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Apoptose / Neuroblastoma Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Apoptose / Neuroblastoma Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article