IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

Matthew N. Svalina, Ken Kikuchi, Jinu Abraham, Sangeet Lal, Monika Davare, Teagan P. Settelmeyer, Michael C. Young, Jennifer L. Peckham, Yoon-Jae Cho, Joel E. Michalek, Brian S. Hernandez, Noah E. Berlow, Melanie Jackson, Daniel J. Guillaume, Nathan Selden, Darell D. Bigner, Kellie Nazemi, Sarah C. Green, Christopher Corless, Sakir GultekinAtiya Mansoor, Brian P. Rubin, Randall (Randy) Woltjer, Charles Keller

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article number27012
JournalScientific Reports
Volume6
DOIs
StatePublished - Jun 3 2016

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Medulloblastoma
Peptide Hydrolases
Cerebrospinal Fluid
Neoplasm Metastasis
Plasminogen Activator Inhibitor 1
Conditioned Culture Medium
Matrix Metalloproteinases
Intercellular Signaling Peptides and Proteins
Phosphorylation
Clinical Trials
Cytokines
Morbidity
Mortality
Growth

ASJC Scopus subject areas

  • General

Cite this

Svalina, M. N., Kikuchi, K., Abraham, J., Lal, S., Davare, M., Settelmeyer, T. P., ... Keller, C. (2016). IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma. Scientific Reports, 6, [27012]. https://doi.org/10.1038/srep27012

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma. / Svalina, Matthew N.; Kikuchi, Ken; Abraham, Jinu; Lal, Sangeet; Davare, Monika; Settelmeyer, Teagan P.; Young, Michael C.; Peckham, Jennifer L.; Cho, Yoon-Jae; Michalek, Joel E.; Hernandez, Brian S.; Berlow, Noah E.; Jackson, Melanie; Guillaume, Daniel J.; Selden, Nathan; Bigner, Darell D.; Nazemi, Kellie; Green, Sarah C.; Corless, Christopher; Gultekin, Sakir; Mansoor, Atiya; Rubin, Brian P.; Woltjer, Randall (Randy); Keller, Charles.

In: Scientific Reports, Vol. 6, 27012, 03.06.2016.

Research output: Contribution to journalArticle

Svalina, MN, Kikuchi, K, Abraham, J, Lal, S, Davare, M, Settelmeyer, TP, Young, MC, Peckham, JL, Cho, Y-J, Michalek, JE, Hernandez, BS, Berlow, NE, Jackson, M, Guillaume, DJ, Selden, N, Bigner, DD, Nazemi, K, Green, SC, Corless, C, Gultekin, S, Mansoor, A, Rubin, BP, Woltjer, RR & Keller, C 2016, 'IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma', Scientific Reports, vol. 6, 27012. https://doi.org/10.1038/srep27012
Svalina MN, Kikuchi K, Abraham J, Lal S, Davare M, Settelmeyer TP et al. IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma. Scientific Reports. 2016 Jun 3;6. 27012. https://doi.org/10.1038/srep27012
Svalina, Matthew N. ; Kikuchi, Ken ; Abraham, Jinu ; Lal, Sangeet ; Davare, Monika ; Settelmeyer, Teagan P. ; Young, Michael C. ; Peckham, Jennifer L. ; Cho, Yoon-Jae ; Michalek, Joel E. ; Hernandez, Brian S. ; Berlow, Noah E. ; Jackson, Melanie ; Guillaume, Daniel J. ; Selden, Nathan ; Bigner, Darell D. ; Nazemi, Kellie ; Green, Sarah C. ; Corless, Christopher ; Gultekin, Sakir ; Mansoor, Atiya ; Rubin, Brian P. ; Woltjer, Randall (Randy) ; Keller, Charles. / IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma. In: Scientific Reports. 2016 ; Vol. 6.
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