Malignant glioma, the most common primary brain tumor subtype, is aggressive and neurologically destructive. The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. Little is known about the molecular mechanisms underlying GBM oncogenesis. The malignant phenotype of human GBM may be driven by GBM-derived stem-like cells (GSCs). One of the key issues for our understanding of cancer stem cells is to define the molecular circuitry that drives the development and self-renewal of the cancer stem cells. Based on our recent experimental results, we propose to evaluate the novel hypothesis that FoxM1, which is abnormally expressed in human GBM-derived stem-like cells (GSCs), causes a high self-renewal rate in the """"""""stem-like"""""""" cells present in the tumor, possibly through a PDGF-A-mediated mechanism, and, thus contribute to tumorigenicity. Here, we propose to evaluate the oncogenic function of FoxM1 in cooperation with p53 tumor suppressor gene in oncogenesis of neural stem cells;and the essential role of FoxM1 in maintaining the characteristics of glioma stem-like cells. If the Specific Aims of this grant application are completed, not only will we understand a new mechanism of GBM molecular oncogenesis through abnormal maintenance of GBM-derived cancer """"""""stem"""""""" cell self-renewal via FoxM1 expression, but also will we learn whether FoxM1 can serve as potential therapeutic targets. This information will have potentially high translational impact. In the long term, our study may lead to the validation of molecular targets that can be used in designing effective strategies to control this deadly disease in clinics.

Public Health Relevance

The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. If the Specific Aims of this grant application are completed, not only will we understand a new mechanism of GBM tumorigenesis through abnormal maintenance of GBM-derived cancer """"""""stem"""""""" cell self-renewal via FoxM1, but we will also learn whether FoxM1 or its target PDGF-A can function as potential therapeutic targets. This information will have potential translational impact. In the long term, our study may lead to the identification of molecular targets that can be used in designing effective strategies to control this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA152623-02
Application #
8094270
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2010-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$166,671
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurosurgery
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Gong, Ai-Hua; Wei, Ping; Zhang, Sicong et al. (2015) FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells. Cancer Res 75:2337-48
Wang, Zhongyong; Zhang, Sicong; Siu, Timothy L et al. (2015) Glioblastoma multiforme formation and EMT: role of FoxM1 transcription factor. Curr Pharm Des 21:1268-71
Xue, Jianfei; Lin, Xia; Chiu, Wen-Tai et al. (2014) Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-?-dependent cancer metastasis. J Clin Invest 124:564-79
Dai, Bingbing; Gong, Aihua; Jing, Zhitao et al. (2013) Forkhead box M1 is regulated by heat shock factor 1 and promotes glioma cells survival under heat shock stress. J Biol Chem 288:1634-42
Gong, Aihua; Huang, Suyun (2012) FoxM1 and Wnt/?-catenin signaling in glioma stem cells. Cancer Res 72:5658-62
Zhang, Nu; Wu, Xinjian; Yang, Lixuan et al. (2012) FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin Cancer Res 18:5961-71
Zhang, Nu; Wei, Ping; Gong, Aihua et al. (2011) FoxM1 promotes ýý-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell 20:427-42