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

Research output: Contribution to journalArticlepeer-review

8 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 languageEnglish (US)
Article number27012
JournalScientific reports
Volume6
DOIs
StatePublished - 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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