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Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model.
Iyer, Radhika; Wehrmann, Lea; Golden, Rebecca L; Naraparaju, Koumudi; Croucher, Jamie L; MacFarland, Suzanne P; Guan, Peng; Kolla, Venkatadri; Wei, Ge; Cam, Nicholas; Li, Gang; Hornby, Zachary; Brodeur, Garrett M.
Afiliación
  • Iyer R; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Wehrmann L; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Golden RL; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Naraparaju K; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Croucher JL; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • MacFarland SP; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Guan P; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Kolla V; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Wei G; The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Cam N; The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Li G; The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Hornby Z; The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Brodeur GM; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Ignyta Inc., San Diego, CA 92121, USA. Electronic address: brodeur@email.chop.edu.
Cancer Lett ; 372(2): 179-86, 2016 Mar 28.
Article en En | MEDLINE | ID: mdl-26797418
Neuroblastoma (NB) is one of the most common and deadly childhood solid tumors. These tumors are characterized by clinical heterogeneity, from spontaneous regression to relentless progression, and the Trk family of neurotrophin receptors plays an important role in this heterogeneous behavior. We wanted to determine if entrectinib (RXDX-101, Ignyta, Inc.), an oral Pan-Trk, Alk and Ros1 inhibitor, was effective in our NB model. In vitro effects of entrectinib, either as a single agent or in combination with the chemotherapeutic agents Irinotecan (Irino) and Temozolomide (TMZ), were studied on an SH-SY5Y cell line stably transfected with TrkB. In vivo growth inhibition activity was studied in NB xenografts, again as a single agent or in combination with Irino-TMZ. Entrectinib significantly inhibited the growth of TrkB-expressing NB cells in vitro, and it significantly enhanced the growth inhibition of Irino-TMZ when used in combination. Single agent therapy resulted in significant tumor growth inhibition in animals treated with entrectinib compared to control animals [p < 0.0001 for event-free survival (EFS)]. Addition of entrectinib to Irino-TMZ also significantly improved the EFS of animals compared to vehicle or Irino-TMZ treated animals [p < 0.0001 for combination vs. control, p = 0.0012 for combination vs. Irino-TMZ]. We show that entrectinib inhibits growth of TrkB expressing NB cells in vitro and in vivo, and that it enhances the efficacy of conventional chemotherapy in in vivo models. Our data suggest that entrectinib is a potent Trk inhibitor and should be tested in clinical trials for NBs and other Trk-expressing tumors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Benzamidas / Proteínas Tirosina Quinasas / Glicoproteínas de Membrana / Protocolos de Quimioterapia Combinada Antineoplásica / Inhibidores de Proteínas Quinasas / Indazoles / Neuroblastoma Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Lett Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Irlanda
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Benzamidas / Proteínas Tirosina Quinasas / Glicoproteínas de Membrana / Protocolos de Quimioterapia Combinada Antineoplásica / Inhibidores de Proteínas Quinasas / Indazoles / Neuroblastoma Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Lett Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Irlanda