title: Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination.
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.
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Jungoh
authors: J
authors: Ham
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Carlotta
authors: C
authors: Costa
authors: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Renata
authors: R
authors: Sano
authors: Department of Microbiology and Immunology, Massey Cancer Center, Richmond, VA 23298, USA.
authors: Timothy L
authors: TL
authors: Lochmann
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Erin M
authors: EM
authors: Sennott
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Neha U
authors: NU
authors: Patel
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Anahita
authors: A
authors: Dastur
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Maria
authors: M
authors: Gomez-Caraballo
authors: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Kateryna
authors: K
authors: Krytska
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Aaron N
authors: AN
authors: Hata
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Konstantinos V
authors: KV
authors: Floros
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Mark T
authors: MT
authors: Hughes
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Charles T
authors: CT
authors: Jakubik
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Daniel A R
authors: DA
authors: Heisey
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Justin T
authors: JT
authors: Ferrell
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Molly L
authors: ML
authors: Bristol
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Ryan J
authors: RJ
authors: March
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Craig
authors: C
authors: Yates
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Mark A
authors: MA
authors: Hicks
authors: Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki 211-8533, Japan.
authors: Wataru
authors: W
authors: Nakajima
authors: Department of Pediatrics, Children's Hospital of Richmond, VCU, Richmond, VA 23298, USA.
authors: Madhu
authors: M
authors: Gowda
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Brad E
authors: BE
authors: Windle
authors: Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Mikhail G
authors: MG
authors: Dozmorov
authors: Cancer Genome Project, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors: Mathew J
authors: MJ
authors: Garnett
authors: Cancer Genome Project, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors: Ultan
authors: U
authors: McDermott
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Hisashi
authors: H
authors: Harada
authors: Department of Microbiology and Immunology, Massey Cancer Center, Richmond, VA 23298, USA.
authors: Shirley M
authors: SM
authors: Taylor
authors: Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
authors: Iain M
authors: IM
authors: Morgan
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Cyril H
authors: CH
authors: Benes
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Jeffrey A
authors: JA
authors: Engelman
authors: 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.
authors: Yael P
authors: YP
authors: Mossé
authors: 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.
authors: Anthony C
authors: AC
authors: Faber
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D013449:Sulfonamides; C528561:navitoclax