High-grade gliomas have one of worst prognoses among all types of human cancers and the efficacy of current therapies remains poor. We are interested in the role of the NF-?B transcription factor family as a key regulator of glioma cancer stem cells (CSCs), which are proposed to give rise to tumor cell heterogeneity and invasive growth. To-date, anti-NF-?B cancer therapy strategies have focused on targeting canonical NF-?B (RelA/IKK?) activation without consideration of the non-canonical NF-?B pathway (RelB/IKK?). Based on our recent findings that RelB promotes oncogenesis in mesenchymal glioma (Lee et al. PLOS One, 2013), we argue that there is a critical need to understand how specific NF-?B signaling pathways contribute to tumor initiation/ progression. Specifically, we propose that canonical and non-canonical NF-?B signaling may be particularly important in different glioma subtypes, as well as distinct cancer stem cell populations. Recent studies suggest an intimate relationship between transforming growth factor ? (TGF?)-induced epithelial-to-mesenchymal transition (EMT) and CSCs survival and invasion. However, the role of EMT and CSC survival in glioma is unclear. Based on preliminary data, we propose to 1) determine which NF-?B proteins and upstream signaling pathways are activated in different glioma subtypes and CSCs;2) evaluate the role of specific NF-?B proteins in promoting self-renewal and pluripotency in distinct CSC populations;and 3) test the effects of inhibiting IKK/NF-?B on glioma CSC survival, invasion and tumor growth in vivo. A better understanding of the mechanisms regulating glioma stem-cell self-renewal and differentiation will not only reveal new insights into glioma tumor biology, but will also facilitate identifying novel approache to target the key cells responsible for tumor heterogeneity and treatment resistance.

Public Health Relevance

High-grade gliomas have one of worst prognoses among all types of human cancers, and the efficacy of current therapies remains poor. There is a critical need to understand the regulatory networks that contribute to tumor initiation/progression, the diversity of glioma subtypes and heterogeneity of distinct cell types within the same tumor. Our project seeks to define the specific functions of NF-?B proteins in promoting these aspects of glioma pathogenesis, which will establish a new framework for the design of new therapeutic strategies for glioma, as well as other cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS082554-01A1
Application #
8697269
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Fountain, Jane W
Project Start
2014-03-15
Project End
2017-02-28
Budget Start
2014-03-15
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$294,973
Indirect Cost
$76,223
Name
Texas A&M University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845