GBM remains the most lethal brain cancer with no effective therapeutics. It has been shown that the majority of stromal cells in GBM are tumor-associated macrophages (TAMs), which contribute to tumor microenvironment heterogeneity and promote GBM progression. We have recently defined molecular pathways leading to macrophage recruitment and polarization. Our preliminary data showed that PTEN mutation/deletion in GBM triggers immune response by enhancing macrophage recruitment through LOX. In addition, we have also identified TBK1 as a key signaling node regulating macrophage polarization.
Aim 1 : we will elucidate the mechanism of LOX mediated macrophage recruitment in GBM;
Aim 2 : we will determine the molecular basis of TBK1 mediated macrophage polarization in GBM;
Aim 3 : we will perform preclinical trials targeting LOX and TBK1 in combination with standard of care and immune checkpoint blockade to develop novel therapeutic approach for GBM patients.

Public Health Relevance

s GBM is heavily infiltrated by tumor promoting macrophage through mechanisms still poorly understood. We have now identified two key therapeutic targets (LOX and TBK1) involved in macrophage recruitment and polarization, respectively, and preclinical therapeutic trials will be performed following detailed mechanistic characterization of novel LOX and TBK1 pathways.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA231349-01A1
Application #
9738487
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Hildesheim, Jeffrey
Project Start
2019-04-01
Project End
2024-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030