IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma.

Conference Paper

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.

Full Text

Duke Authors

Cited Authors

  • Svalina, MN; Kikuchi, K; Abraham, J; Lal, S; Davare, MA; Settelmeyer, TP; Young, MC; Peckham, JL; Cho, Y-J; Michalek, JE; Hernandez, BS; Berlow, NE; Jackson, M; Guillaume, DJ; Selden, NR; Bigner, DD; Nazemi, KJ; Green, SC; Corless, CL; Gultekin, S; Mansoor, A; Rubin, BP; Woltjer, R; Keller, C

Published Date

  • June 3, 2016

Published In

Volume / Issue

  • 6 /

Start / End Page

  • 27012 -

PubMed ID

  • 27255663

Pubmed Central ID

  • PMC4891740

Electronic International Standard Serial Number (EISSN)

  • 2045-2322

Digital Object Identifier (DOI)

  • 10.1038/srep27012

Conference Location

  • England