Astrocytomas are the most common primary brain tumors and account for more than 60% of all primary central nervous system (CMS) neoplasms. The most malignant form of astrocytoma (grade IV astrocytoma), also known as glioblastoma multiforme (GBM), is 1 of the most aggressive human cancers with a median survival of less than 1 year. Unfortunately, this prognosis has not changed significantly over the past 2 decades, despite advances in neurosurgery, radiation and chemotherapy. 2 characteristic features of malignant astrocytomas play a major role in defining the deadly nature of the disease. First, unlike most human solid tumors, astrocytoma cells extensively invade normal brain tissue even at the low-grade stage, which essentially prevents surgical cure. Second, low-grade astrocytomas have a high propensity to transform into GBMs, which are resistant to all of the current therapeutic modalities. Thus, 1 of the major challenges for treating malignant astrocytomas is to understand the cellular and molecular basis that underlies the highly invasive nature of astrocytoma cells. Particularly, (1) it remains elusive what cell type(s) in the brain gives rise to malignant astrocytoma, (2) insights have been slower to emerge regarding how the specific genetic defects contribute to the abnormal phenotypic traits of astrocytoma cells, despite recent advances in the identification of genetic lesions associated with the development of malignant astrocytomas. Thus, the goals of the specific aims described in this proposal is to use genetic, molecular and cellular approaches to determine whether neural stem cells (NSCs) in the adult brain are the cell-of-origin for malignant astrocytoma. Specifically, we will determine (1) whether tumor suppressors p53 and Neurofibromatosis type 1 (NF1) play physiological roles in regulating NSC proliferation, apoptosis and differentiation in the adult brain and (2) whether malignant astrocytoma can be induced when p53 and NF1 mutations are specifically targeted into NSCs in the adult brain. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053900-03
Application #
7432528
Study Section
Special Emphasis Panel (ZRG1-ONC-U (90))
Program Officer
Fountain, Jane W
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$309,361
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109