Glioblastoma (GBM) is the most common primary brain tumor in adults and one of the most lethal of all cancers, with a median patient survival of 12-15 months despite advanced treatment. There is no effective therapeutic strategy to antagonize GBM malignant growth. Therefore, identification of new molecular targets and development of innovative treatment strategies are desperately needed. EGFR/PI3K/Akt signaling has been shown to be activated in around 88% of GBM patients, which suggests that it could be a promising therapeutic strategy to target this pathway to treat GBM. Unfortunately, targeting EGFR, PI3K and mTOR using its small molecular inhibitors has shown no or very short-term response. To significantly improve the efficacy of GBM treatment, it is essential to better understand the underlying molecular mechanisms of GBM pathogenesis and its biologic characteristics. Metabolism reprogramming has been shown to coordinate with oncogenic growth signaling and promote rapid tumor growth. However, the detailed mechanisms of metabolic changes and their molecular links with oncogenic signaling are still unclear. Our previous study was the first to demonstrate that fatty acid synthesis is highly elevated in GBM and is upregulated by EGFR/PI3K/Akt signaling through activation of sterol regulatory element-binding protein-1 (SREBP-1), a master lipogenesis transcriptional factor. In addition to fatty acid cholesterol is also important for cells as it is an essential component of cell membranes. However, whether cholesterol metabolism is altered in cancers remains unknown. Our preliminary data shows that cholesteryl esters and cholesterol-rich low density lipoprotein (LDL) receptor (LDLR) are both highly elevated in GBM cell lines and patient tissues, particularly in EGFRvIII- expressing cells. Our data further demonstrate that GBM cell growth is highly dependent on LDL uptake, and activating nuclear receptor liver X receptor (LXR) significantly inhibits GBM cell growth. The hypothesis of this application is that GBM cells are dependent on cholesterol uptake for rapid growth, and its high levels are maintained by EGFR/PI3K/Akt signaling through upregulation of the SREBP-1/LDLR pathway to promote LDL uptake. We predict that LDLR and LXR are novel molecular targets in GBM and depriving cells of cholesterol alone or in combination with inhibition of fatty acid synthesis will significantly inhiit GBM growth. In this study, we aim to identify a novel therapeutically targetable tumor survival pathway, and investigate the efficacy of targeting LDLR or activating LXR by its synthetic agonists GW3965 and T9091317, separately or in combination with the FASN inhibitor C75 on GBM xenograft tumor growth. We will: 1) determine the molecular mechanism by which EGFR/PI3K signaling upregulates LDLR and LDL uptake, and test atorvastatin treatment in GBM cells in Aim 1;2) investigate the role of LDLR on GBM tumor growth in Aim 2;3) determine the mechanism and efficacy of activating LXR by GW3965, T9091317 alone or in combination with FASN inhibitor C75 on GBM tumor growth, and evaluate the translational potential of these drugs to treat GBM in Aim 3.

Public Health Relevance

Glioblastoma (GBM) is the most common primary brain tumor in adults and one of the most deadly cancers, with a median patient survival of 12-15 months. This application will investigate changes in the cholesterol metabolic pathway in GBM and elucidate its molecular link to the oncogenic signaling EGFR/PI3K/Akt pathway. The study aims to demonstrate that depriving tumor cells of cholesterol, alone or in combination with inhibition of fatty acid synthesis results in GBM cell death. At the completion of this study, new molecular targets will be identified and novel therapeutic strategies will be tested in animal models for ther future translational potential in GBM patients.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS079701-02
Application #
8606783
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
Guo, Deliang; Bell, Erica Hlavin; Mischel, Paul et al. (2014) Targeting SREBP-1-driven Lipid Metabolism to Treat Cancer. Curr Pharm Des 20:2619-26
Guo, Deliang; Bell, Erica Hlavin; Chakravarti, Arnab (2013) Lipid metabolism emerges as a promising target for malignant glioma therapy. CNS Oncol 2:289-299