IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

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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.

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Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

Marcel Kool, Andrey Korshunov, Marc Remke … (2012)

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future. Electronic supplementary material The online version of this article (doi:10.1007/s00401-012-0958-8) contains supplementary material, which is available to authorized users.

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Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.

Amar Gajjar, Murali Chintagumpala, David P Ashley … (2006)

Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. After resection, patients were classified as having average-risk medulloblastoma ( 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

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Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis.

Adam Fontebasso, José Alexandre Coelho Pimentel, Uri Tabori … (2013)

Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 03 June 2016

Publication date Collection: 2016

Volume: 6

Electronic Location Identifier: 27012

Affiliations

[1 ]Children’s Cancer Therapy Development Institute , Beaverton, OR USA

[2 ]Department of Pediatrics, Oregon Health & Science University , Portland, OR 97239 USA

[3 ]Division of Child Neurology, Stanford Medicine Cancer Institute , Palo Alto, CA 94304 USA

[4 ]Department of Epidemiology and Biostatistics, University of Texas Health Science Center , San Antonio, TX 78229 USA

[5 ]Division of Pediatric Neurosurgery, Department of Neurological Surgery, Oregon Health & Science University , Portland, OR 97239 USA

[6 ]Pediatric Brain Tumor Foundation Institute at Duke, Duke University Medical Center , Durham, NC 27705 USA

[7 ]Department of Pathology, Oregon Health & Science University , Portland, OR 97239 USA

[8 ]Departments of Anatomic Pathology and Molecular Genetics, Taussig Cancer Center and Lerner Research Institute, Cleveland Clinic Foundation , Cleveland, OH 44195 USA

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[a ] charles@ 123456cc-tdi.org

Article

Publisher Item ID: srep27012

DOI: 10.1038/srep27012

PMC ID: 4891740

PubMed ID: 27255663

SO-VID: 3f684010-244a-4103-8cd5-11b844dea901

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IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

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Most cited references 44

Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.

Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis.

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