IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

Sci Rep. 2016 Jun 3:6:27012. doi: 10.1038/srep27012.

Abstract

Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / cerebrospinal fluid
  • Biomarkers, Tumor / genetics
  • Case-Control Studies
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cerebellar Neoplasms / cerebrospinal fluid*
  • Cerebellar Neoplasms / drug therapy
  • Cerebellar Neoplasms / pathology
  • Child
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Expression
  • Humans
  • Inhibitory Concentration 50
  • Insulin-Like Growth Factor Binding Protein 3 / cerebrospinal fluid
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor I / cerebrospinal fluid
  • Insulin-Like Growth Factor I / genetics
  • Male
  • Matrix Metalloproteinase 9 / cerebrospinal fluid
  • Matrix Metalloproteinase 9 / genetics
  • Medulloblastoma / cerebrospinal fluid*
  • Medulloblastoma / drug therapy
  • Medulloblastoma / secondary
  • Meningeal Neoplasms / cerebrospinal fluid*
  • Meningeal Neoplasms / drug therapy
  • Meningeal Neoplasms / secondary
  • Molecular Targeted Therapy
  • Plasminogen Activator Inhibitor 1 / cerebrospinal fluid
  • Plasminogen Activator Inhibitor 1 / genetics
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / antagonists & inhibitors
  • Receptors, Somatomedin / genetics
  • Receptors, Somatomedin / metabolism*
  • Tissue Inhibitor of Metalloproteinase-1 / cerebrospinal fluid
  • Tissue Inhibitor of Metalloproteinase-1 / genetics

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • IGF1 protein, human
  • IGF1R protein, human
  • IGFBP3 protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • Plasminogen Activator Inhibitor 1
  • Receptors, Somatomedin
  • SERPINE1 protein, human
  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • MMP9 protein, human
  • Matrix Metalloproteinase 9