This application is for the renewal of a Program Project that endeavors to improve understanding of the pathogenesis of glioblastoma multiforme (GBM). The Program comprises an interdisciplinary team of basic, translational and clinical scientists with a strong track record of working together and strengths in tumor biology, mouse genetics, genomics/informatics, and experimental pathology. This team will (i) dissect the role of GBM signature mutations in governing the tumor biological properties of the disease using a variety of model systems, (ii) identify, validate and characterize new GBM oncogenes and tumor suppressors, (iii) illuminate and validate the role of the EGFR-PI3K pathway in GBM using an array of genetic approaches, (iv) define and therapeutically manipulate key signaling molecules such as receptor and non-receptor tyrosine kinases in sophisticated genetically defined mouse and human models, and (v) understand how these newly discovered genetic elements modulate the response to EGFR inhibition. The Program consists of 3 Projects and 4 Cores that together encompass state-of-the-art genetic engineering, superb experimental pathology and biospecimen repositories, and extraordinary genomic and functional validation capabilities that will enable the team to provide a dynamic analysis of GBM biology and signaling in unprecedented detail. Project 1 will focus on the refinement of a unique high-grade glioma model, developed in the first period of the Program, by incorporating newly discovered glioma-relevant alleles emerging from genetic, functional genomic and proteomic studies throughout the Program. Project 2 exploits biochemical and cell biological analyses that are designed to understand activated EGFR signaling in GBM and how patients respond or progress when treated with EGFR kinase inhibitors. Project 3 is new to the renewal and combines strengths in pncogenomics and high throughput RNA interference with which they will identify a set of putative oncogenes that are not only amplified in GBM but also necessary for their proliferation and survival. Core A will provide Program investigators with sophisticated mouse modeling of mutations as well as an exceptional biorepository of astrocytes, neural stem cells, neurospheres and patient specimens. Core B will provide critical neuropathologic analyses of mouse and human tumor tissues. Core C will continue to provide critical genomics infrastructure and capabilities as well as essential computational and biostatistical support. Core D will provide the administrative oversight necessary to assure efficient and effective use of the Program resources. The long-term goal of these basic and preclinical efforts is to leverage institutional and other resources with the P01 in order to provide substantial synergies for pushing basic disease-related discovery to translation and in identifying and guiding opportunities for targeted drug discovery in this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA095616-10
Application #
8234817
Study Section
Special Emphasis Panel (ZCA1-GRB-S (O1))
Program Officer
Woodhouse, Elizabeth
Project Start
2002-04-01
Project End
2014-02-28
Budget Start
2012-08-09
Budget End
2014-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$2,252,010
Indirect Cost
$546,386
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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