Presentation Abstract

Abstract Number: 2480
Presentation Title: High-level activation of the Notch pathway in diffuse intrinsic pontine glioma
Presentation Time: Monday, Apr 02, 2012, 1:00 PM - 5:00 PM
Location: McCormick Place West (Hall F), Poster Section 18
Poster Section: 18
Poster Board Number: 5
Author Block: Marianne Hutt1, Kah Jing Lim1, Katherine Warren2, Howard T. Chang3, Charles G. Eberhart1, Eric H. Raabe4. 1Johns Hopkins University Division of Neuropathology, Baltimore, MD; 2National Institute of Health, Pediatric Oncology Branch, Bethesda, MD; 3Michigan State University Department of Neurology and Ophthalmology, East Lansing, MI; 4Johns Hopkins University, Division of Pediatric Oncology, Baltimore, MD
Abstract Body: Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor. Due to its critical location within the brainstem, and its characteristic MRI signature, biopsy is rarely performed. Since many patients die at home in hospice care, autopsy specimens have traditionally been rare. Because of this difficulty in obtaining tissue, three institutions (Johns Hopkins, Children's National Medical Center, and the National Institutes of Health - Pediatric Oncology Branch) have formed the Mid-Atlantic DIPG Consortium (MADC), to collect and disseminate rapid-autopsy material from patients with DIPG. Using a fresh tissue specimen obtained from a rapid autopsy and disseminated through the MADC, we have established a human DIPG xenograft and neurosphere cell line, JHH-DIPG1. In vitro, these cells are GFAP positive and express human neural stem cell markers often observed in glioblastoma, including human specific SOX2 and NESTIN. They also show marked invasive properties in vitro as measured by transwell invasion assay. In vivo, JHH-DIPG1 forms tumor xenografts in approximately six months in immunocompromised mice. Tumor cells diffusely infiltrate distant brain structures, recapitulating the invasive phenotype of DIPG. Due to their high level expression of neural stem cell markers, and the well-known roles of the Notch pathway in stem cell biology and aggressive brain tumors, we examined the expression of members of the Notch pathway in DIPG. Notch downstream effectors, specifically Hes1, Hes5 and Hey1, are highly expressed in JHH-DIPG1, at levels equal to or exceeding those observed in neurosphere cell lines derived from adult supratentorial glioblastoma. The JHH-DIPG1 tumor cell line represents one of only a handful of pediatric DIPG cell lines extant, and the high level of Notch pathway activation in these cells suggests that blockade of the Notch pathway using gamma secretase inhibitors and shRNAs against the canonical Notch effector CBF may be efficacious in DIPG. Our laboratory is actively investigating the role of the Notch pathway in DIPG using this and other DIPG cell lines, with the goal of moving Notch inhibition into clinical trials for these currently highly lethal tumors.