In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 2056-2056
Abstract:
2056 Background: Medulloblastoma survival rates have significantly improved over the last decades due to surgery and chemoradiation regimens. However, pediatric patients with high-risk disease and those with recurrence often succumb to their disease. The majority of children suffer from severe adverse effects of intense therapy regimens. We recently demonstrated the role of the Placental Growth Factor (PlGF)/Nrp-1 signaling pathway in medulloblastoma progression in preclinical models (Snuderl et al., Cell 2013). The aim of this study was to evaluate the role of Nrp-1 as a biomarker and therapeutic target in medulloblastoma patients. Methods: Thirty-two surgical samples of pediatric medulloblastoma were analyzed for expression of Nrp-1 and its ligand PlGF by immunohistochemistry, array-comparative genomic hybridization and deep gene sequencing. On an independent, clinically annotated cohort of 42 medulloblastoma samples, we evaluated the correlation between Nrp-1 expression and 5-year overall survival. The therapeutic relevance of Nrp-1 signaling was tested in a D283 orthotopic human xenograft mouse model using shRNA and a monoclonal antibody against Nrp-1. Results: Nrp-1 expression was detectable in 100% and PlGF in 90% of all medulloblastoma samples. No significant differences in expression could be detected between known histological or molecular medulloblastoma subtypes. Patients with high Nrp-1 expression had a significantly worse 5-year overall survival compared to patients with a low or moderate expression (40% vs. 86%, p = 0.0058). Treatment with an antibody against Nrp-1 or genetic silencing of Nrp-1 with shRNA significantly prolonged survival in a D283 orthotopic human xenograft mouse model (for both experiments: p 〈 0.01). Conclusions: Nrp-1 is widely expressed across all molecular subgroups of medulloblastoma and its expression levels are inversely associated with survival of patients. Targeting Nrp-1 leads to a significant survival benefit in an orthotopic human xenograft mouse model. This data support the hypothesis that targeting the PlGF/Nrp-1 signaling pathway may be a novel therapy approach for pediatric medulloblastoma.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.2056
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
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