Evidence has been accumulating over recent years linking cytomegalovirus (CMV) to glioblastoma and other cancers. To improve our understanding of the mechanisms underlying the link between CMV and GBM, we have developed a murine model of CMV-mediated glioma oncomodulation. We have shown that perinatal murine CMV (MCMV) infection accelerates glioma progression and significantly shortens survival in mice with somatic p53 heterozygosity and conditional Nf1 mutations in GFAP-expressing cells in the brain (mut 3 mice). Our published and pilot data suggests that MCMV activates a PDGFB/STAT3 signaling axis in brains and tumors. In addition, it shows that CD45 lymphocytes within gliomas express MCMV antigens. Coupled with recent exciting human clinical trial data that seems to show encouraging effects of antiCMV therapies in humans with GBM, these results do lend credence to the hypothesis that CMV plays a modulatory role in GBM pathology. Our unique mouse model allows us to propose additional hypotheses in this context. Specifically, we speculate that MCMV leads to PDGF/STAT3 activation in brains before glioma formation and to immunosuppressive effects in trafficking immune cells, leading to the observed acceleration of GBM pathology. Based on this, antiCMV therapies targeting these pathways may thus lead to significant antiGBM effects in Mut3 mice. To test these hypotheses, we thus propose the following aims:
Specific Aim 1 - Identify mediators of the pro-oncogenic effects of MCMV in glioma stem-like cells. Hypothesis: MCMV leads to up regulation of PDGF and STAT3 signaling in GBM stem-like cells (GSCs) and neural stem cells (NSCs), promoting GBM precursor self-renewal. Impact: Successful completion of this aim will increase our understanding of the signaling pathways that are affected by MCMV in GSCs and NSCs, providing a clear rationale for therapeutic targeting.
Specific Aim 2 - Identify cell populations that harbor MCMV intratumorally and systemically. Hypothesis: MCMV is predominantly expressed in specific types of cells which mediate its effects. Impact: Identification of the cell population(s) harboring MCMV in tumors will allow increased understanding and development of approaches to target CMV in GBM.
Specific Aim 3 - Investigate therapeutic targeting of CMV in the model. Hypothesis: CMV infection presents opportunities for therapeutic intervention in GBM. Impact: Completion of this aim will inform on the potential of therapeutic intervention in GBM through specifically targeting MCMV related processes.

Public Health Relevance

Recent data has identified the presence of cytomegalovirus DNA, RNA and protein in tumor samples from human glioblastoma patients. We have recently developed the first murine model cytomegalovirus in glioblastoma and found that viral infection promotes accelerated tumor formation. Therefore, in this project we will use this model to further understand the biology underlying this observation and identify approaches to improve glioblastoma treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA195532-04
Application #
9438493
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Daschner, Phillip J
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Price, Richard L; Song, Jieun; Bingmer, Katherine et al. (2013) Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations. Cancer Res 73:3441-50
Price, Richard L; Bingmer, Katherine; Harkins, Lualhati et al. (2012) Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53+/- mice. Cancer Res 72:5669-74