IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

Matthew N. Svalina; Ken Kikuchi; Jinu Abraham; Sangeet Lal; Monika A. 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 R. Selden; Darell D. Bigner; Kellie J. Nazemi; Sarah C. Green; Christopher L. Corless; Sakir Gultekin; Atiya Mansoor; Brian P. Rubin; Randall Woltjer; Charles Keller

doi:10.1038/srep27012

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

Matthew N. Svalina, Ken Kikuchi, Jinu Abraham, Sangeet Lal, Monika A. 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 R. Selden, Darell D. Bigner, Kellie J. Nazemi, Sarah C. Green, Christopher L. Corless, Sakir GultekinAtiya Mansoor, Brian P. Rubin, Randall Woltjer, Charles Keller

Neurosurgery

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20 Scopus citations

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 language	English (US)
Article number	27012
Journal	Scientific reports
Volume	6
DOIs	https://doi.org/10.1038/srep27012
State	Published - Jun 3 2016

Bibliographical note

Funding Information:
Different aspects of these studies were supported by a pilot research grant fund from the 2P30CA069533-14, a gift from Matthew Nelson in honor of Wesley by way of the Wesley's Cure for Cancer Research Foundation (WCCRF) for medulloblastoma research, funds provided to the Knight Cancer Institute at Oregon Health Sciences University by the Schnitzer Investment Corporation and programmatic support of the Rally Foundation. Key equipment was made possible by gifts from the Kyla McCullough Gift Fund. We thank Nancy Goodman, whose critical questions inspired these studies.

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Svalina, M. N., Kikuchi, K., Abraham, J., Lal, S., Davare, M. A., Settelmeyer, T. P., Young, M. C., Peckham, J. L., Cho, Y. J., Michalek, J. E., Hernandez, B. S., Berlow, N. E., Jackson, M., Guillaume, D. J., Selden, N. R., Bigner, D. D., Nazemi, K. J., Green, S. C., Corless, C. L., ... Keller, C. (2016). IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma. Scientific reports, 6, Article 27012. https://doi.org/10.1038/srep27012

Svalina, MN, Kikuchi, K, Abraham, J, Lal, S, Davare, MA, Settelmeyer, TP, Young, MC, Peckham, JL, Cho, YJ, 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 2016, 'IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma', Scientific reports, vol. 6, 27012. https://doi.org/10.1038/srep27012

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title = "IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma",

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.",

author = "Svalina, {Matthew N.} and Ken Kikuchi and Jinu Abraham and Sangeet Lal and Davare, {Monika A.} and Settelmeyer, {Teagan P.} and Young, {Michael C.} and Peckham, {Jennifer L.} and Cho, {Yoon Jae} and Michalek, {Joel E.} and Hernandez, {Brian S.} and Berlow, {Noah E.} and Melanie Jackson and Guillaume, {Daniel J.} and Selden, {Nathan R.} and Bigner, {Darell D.} and Nazemi, {Kellie J.} and Green, {Sarah C.} and Corless, {Christopher L.} and Sakir Gultekin and Atiya Mansoor and Rubin, {Brian P.} and Randall Woltjer and Charles Keller",

note = "Funding Information: Different aspects of these studies were supported by a pilot research grant fund from the 2P30CA069533-14, a gift from Matthew Nelson in honor of Wesley by way of the Wesley's Cure for Cancer Research Foundation (WCCRF) for medulloblastoma research, funds provided to the Knight Cancer Institute at Oregon Health Sciences University by the Schnitzer Investment Corporation and programmatic support of the Rally Foundation. Key equipment was made possible by gifts from the Kyla McCullough Gift Fund. We thank Nancy Goodman, whose critical questions inspired these studies.",

year = "2016",

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doi = "10.1038/srep27012",

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T1 - IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

AU - Svalina, Matthew N.

AU - Kikuchi, Ken

AU - Abraham, Jinu

AU - Lal, Sangeet

AU - Davare, Monika A.

AU - Settelmeyer, Teagan P.

AU - Young, Michael C.

AU - Peckham, Jennifer L.

AU - Cho, Yoon Jae

AU - Michalek, Joel E.

AU - Hernandez, Brian S.

AU - Berlow, Noah E.

AU - Jackson, Melanie

AU - Guillaume, Daniel J.

AU - Selden, Nathan R.

AU - Bigner, Darell D.

AU - Nazemi, Kellie J.

AU - Green, Sarah C.

AU - Corless, Christopher L.

AU - Gultekin, Sakir

AU - Mansoor, Atiya

AU - Rubin, Brian P.

AU - Woltjer, Randall

AU - Keller, Charles

N1 - Funding Information: Different aspects of these studies were supported by a pilot research grant fund from the 2P30CA069533-14, a gift from Matthew Nelson in honor of Wesley by way of the Wesley's Cure for Cancer Research Foundation (WCCRF) for medulloblastoma research, funds provided to the Knight Cancer Institute at Oregon Health Sciences University by the Schnitzer Investment Corporation and programmatic support of the Rally Foundation. Key equipment was made possible by gifts from the Kyla McCullough Gift Fund. We thank Nancy Goodman, whose critical questions inspired these studies.

PY - 2016/6/3

Y1 - 2016/6/3

N2 - 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.

AB - 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.

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DO - 10.1038/srep27012

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ER -

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

Abstract

Bibliographical note

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