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.
authors.affiliation: Children's Cancer Therapy Development Institute, Beaverton, OR USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Svalina
authors.affiliation: Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Jinu
authors.initials: J
authors.lastname: Abraham
authors.affiliation: Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Sangeet
authors.initials: S
authors.lastname: Lal
authors.affiliation: Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Davare
authors.affiliation: Children's Cancer Therapy Development Institute, Beaverton, OR USA.
authors.forename: Teagan P
authors.initials: TP
authors.lastname: Settelmeyer
authors.affiliation: Children's Cancer Therapy Development Institute, Beaverton, OR USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Young
authors.affiliation: Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Peckham
authors.affiliation: Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.|Division of Child Neurology, Stanford Medicine Cancer Institute, Palo Alto, CA 94304 USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229 USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229 USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Hernandez
authors.affiliation: Children's Cancer Therapy Development Institute, Beaverton, OR USA.
authors.forename: Noah E
authors.initials: NE
authors.lastname: Berlow
authors.affiliation: Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Jackson
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurological Surgery, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Guillaume
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurological Surgery, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Selden
authors.affiliation: Pediatric Brain Tumor Foundation Institute at Duke, Duke University Medical Center, Durham, NC 27705 USA.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: Department of Pediatrics, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Kellie J
authors.initials: KJ
authors.lastname: Nazemi
authors.affiliation: Department of Pathology, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Green
authors.affiliation: Department of Pathology, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: Department of Pathology, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Sakir
authors.initials: S
authors.lastname: Gultekin
authors.affiliation: Department of Pathology, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Atiya
authors.initials: A
authors.lastname: Mansoor
authors.affiliation: Departments of Anatomic Pathology and Molecular Genetics, Taussig Cancer Center and Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195 USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Department of Pathology, Oregon Health &Science University, Portland, OR 97239 USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Woltjer
authors.affiliation: Children's Cancer Therapy Development Institute, Beaverton, OR USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000235:genetics; D016022:Case-Control Studies; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000473:pathology; D002648:Child; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000134:cerebrospinal fluid / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000134:cerebrospinal fluid / Q000235:genetics; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid / Q000235:genetics; D008527:Medulloblastoma / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000556:secondary; D008577:Meningeal Neoplasms / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000556:secondary; D058990:Molecular Targeted Therapy; D017395:Plasminogen Activator Inhibitor 1 / Q000134:cerebrospinal fluid / Q000235:genetics; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C583557:IGF1 protein, human; C000597236:IGF1R protein, human; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D017395:Plasminogen Activator Inhibitor 1; D017451:Receptors, Somatomedin; C051321:SERPINE1 protein, human; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9