BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells

J Mol Neurosci. 2016 Jul;59(3):326-33. doi: 10.1007/s12031-015-0689-0. Epub 2015 Nov 27.

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide (ANA-12) markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide the first evidence supporting further investigation of TrkB inhibition as a potential novel strategy for MB treatment.

Keywords: Brain tumor; Brain-derived neurotrophic factor; Childhood cancer; Medulloblastoma; TrkB.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Azepines / pharmacology*
  • Benzamides / pharmacology*
  • Brain Neoplasms / metabolism*
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Humans
  • Medulloblastoma / metabolism*
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Receptor, trkB
  • Signal Transduction

Substances

  • ANA 12 compound
  • Antineoplastic Agents
  • Azepines
  • Benzamides
  • Brain-Derived Neurotrophic Factor
  • Membrane Glycoproteins
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Receptor, trkB
  • tropomyosin-related kinase-B, human