Abstract LB-363: Inhibition of placental growth factor (PlGF) leads to regression of medulloblastoma

Abstract

Abstract Introduction: Medulloblastoma contains a rich and abnormal vascular network offering a potential target for anti-angiogenic treatment. However, in pediatric patients anti-VEGF treatments may have serious adverse effects and other antiangiogenic drugs have not shown efficacy. Placental growth factor (PlGF) is a mediator of post-natal pathological angiogenesis, and its inhibition may not be associated with significant side effects. Here, we examine the role of PlGF in medulloblastoma growth and as a target for therapy in this pediatric brain tumor. Methods: Tissues collected from 5 pediatric medulloblastomas and 4 adult cerebelli were screened for 96 genes associated with angiogenesis using a commercially available PCR array. Immunohistochemistry was performed on 14 formalin fixed paraffin embedded (FFPE) medulloblastoma samples. D283Med and D341Med human medulloblastoma cells were transfected with Gaussia luciferase cDNA and implanted orthotopically into cerebelli of SCID mice. Tumor growth was followed by whole body imaging and blood Gluc assay. Tumor-derived PlGF was blocked by anti-PlGF antibody (PL5D11D4, ThromboGenics) or silenced by siRNA. WST-1 Cell Proliferation Assay was performed to explore direct effects of anti-PlGF Ab in vitro. Results: PlGF was not expressed in adult cerebelli and was overexpressed in all medulloblastomas tissues and cell lines by PCR. Twelve of fourteen (85%) FFPE medulloblastomas showed expression of PlGF by immunohistochemistry. Mice with implanted medulloblastoma cells with PlGF silenced by siRNA or blocked by the antibody from the day of implantation showed a significant delay in tumor growth (p < 0.0001) and prolonged survival (p = 0.003) when compared to control IgG-treated mice. Treatment of established tumors with anti-PlGF antibody - started at ∼3 weeks post-implantation - showed stabilization of disease and regression of medulloblastomas (p = 0.017) by Gluc and whole body imaging measurements, and prolongation of survival (p = 0.0009). However, in vitro we found no direct effect of anti-PlGF treatment on tumor cells. Further mechanistic findings will be presented at the meeting. Conclusion: PlGF is highly expressed in medulloblastomas. Mice bearing orthotopic tumors showed significantly delayed tumor growth and longer survival after PlGF inhibition. Thus, PlGF targeting in these tumors may provide a safe and efficient therapy for pediatric medulloblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-363.