Glioblastoma is highly resistant to chemo- and radiotherapy. Despite treatment, median survival is only 12-15 months. Tumor cells rely upon elevated stress response pathways to survive and maintain a rapid proliferative rate in the harsh tumor microenvironment. Glioblastoma stem cells (GSCs) are particularly enriched in their ability to survive in the context of nutrient deprivation, high reactive oxygen species, DNA damage and radiation. Upregulation of heat shock proteins (HSPs) and the unfolded proteins response (UPR) promote cell survival during stress. These pathways are elevated in glioblastoma and knockdown induces chemosensitivity and cell death. The UPR specifically relieves ER stress, a key pathway of radiation-induced cell death. I have identified RSAD1 as a potential regulator of the UPR and thus a novel dependency in GSCs. There are currently no published studies characterizing the function of RSAD1. RSAD1 is upregulated in glioblastoma and is correlated with worse survival, and my preliminary evidence demonstrates that RSAD1 knockdown significantly impairs proliferation in GSCs. I found that RSAD1 binding partners enrich for UPR regulators and HSPs. The goal of this research is to test the hypothesis that RSAD1 promotes survival in GSCs through activation of the UPR. Given the important role of the UPR in inducing stress resilience, inhibition of RSAD may act as a chemo- or radiosensitizer of GSCs, in addition to independently impairing proliferation. RSAD1 may therefore be a novel target for synergistic therapy in glioblastoma.

Public Health Relevance

Glioblastoma is the most common malignant brain tumor and is highly resistant to therapy. Upregulation of the unfolded protein response (UPR) is hypothesized to increase glioblastoma cell resistance to stress, and my preliminary data have identified RSAD1, a protein of undescribed function, as a potential regulator of the UPR in glioblastoma. The experiments proposed herein will elucidate whether RSAD1 increases resilience of glioblastoma cells, and thus whether it represents a novel target in glioblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30CA217066-01
Application #
9327330
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2017-03-01
Project End
2022-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195