In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4186-4186
Abstract:
Gliomas are among the most lethal human cancers, with high-grade tumors exhibiting a dismal 5-year survival rate. Mutations and amplifications of receptor tyrosine kinases such as PDGFR and EGFR, which drive Ras-MAPK pathway activity, are among the hallmark mutations of adult gliomas. However, pediatric glioblastomas often do not exhibit the oncogenic mutations found in adult tumors, suggesting that these tumors may have distinct mechanistic origins. The unique genetic characteristics of pediatric brain tumors may also affect their response to conventional treatment. Therefore, there is a need to generate mouse models that faithfully recapitulate the genetics of pediatric glioblastomas to identify potential avenues for improving treatment of these tumors. Recent genetic profiling of pediatric brain tumors has found activating mutations of the BRaf kinase in higher grade tumors but not low-grade juvenile pilocytic astrocytomas. By contrast, BRaf is not frequently altered in adult gliomas, suggesting that cells in the developing brain may be particularly susceptible to this mechanism of Ras pathway activation. In addition, BRaf mutation is closely linked to the loss of the tumor suppressor Ink4a/Arf, indicating a possible requirement for loss of this tumor suppressor in the development of high-grade gliomas. Here, we describe the generation of a model system allowing expression of oncogenic BRaf in spatially and temporally defined populations of neural stem cells. In BRaf CA/+; R26YFP animals, Cre-mediated recombination induces expression of the oncogenic V600E mutant form of Braf from the endogenous gene locus and simultaneously labels these cells via expression of YFP. By stereotaxically injecting Cre-expressing adenovirus into the neonatal or adult brain in these mice, we can induce oncogene expression in specific populations of neural progenitors and track its effects on infected cells. Data from multiple tumor types suggests that the activation of Ras-MAPK signaling via BRaf mutation is tightly linked to loss of the Ink4a/Arf tumor suppressor locus. We are also using viral introduction of Cre to activate oncogenic BRaf when Ink4a/Arf expression is absent. The phenotype of these mice will be compared to human pediatric gliomas to determine if this system provides an accurate model of the human disease. Such a model would provide a platform for testing targeted therapies against BRaf - a critical step in designing new treatments for pediatric glioblastoma. 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 4186.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-4186
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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