Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY Glioblastoma (GBM) is a brain tumor that causes neurological deterioration and death in most patients within 2 years. Despite aggressive therapy, most GBMs reappear within 6 months. A major reason for this outcome is because GBM stem cells (GSCs) are resistant to existing therapies. Currently, no treatment consistently kills these highly resistant cells. However, the Zika virus epidemic has provided us with a new approach to eradicate GSCs. ZIKV targets normal stem cells in the developing fetal brain, yet has minimal effects on differentiated neurons or the adult brain. Since GSCs share properties with neural stem cells, we investigated whether the natural honing and lytic activity of ZIKV could be harnessed to target and kill GSCs. We published the first use of ZIKV to kill GSCs. We showed that ZIKV kills GSCs in tumors removed from patients, with minimal impact on non-GSC tumor cells, called differentiated GBM cells. Importantly, normal human brain cells were not affected by ZIKV. After intracranial treatment with ZIKV, mice harboring gliomas survived more than twice as long as untreated mice and, in some cases, treated mice were long-term survivors. In addition to the resistance of GBM stem cell to chemoradiation, GBM is the hallmark example of an immunotherapy-resistant tumor. Importantly, we found that in vivo, ZIKV treatment reduces tumor size and extends survival beyond that expected for only anti-GSC effects. This suggested that ZIKV killing of GSCs may trigger an immune response against the remainder of the tumor. In more recent studies, we have found that CD8+ T cells are required for the efficacy of ZIKV as an oncolytic therapy in vivo. Our central hypothesis is that ZIKV elicits an anti-tumor immune response that could be made even more effective by combining it with existing immunotherapies. Aim 1 will determine how CD8+ T cells promote tumor clearance after ZIKV and Aim 2 will determine whether ZIKV can be combined with immunotherapy or standard-of-care for GBM to improve outcomes. Our long-term goal is to develop a new treatment for GBM by leveraging the immune system response to ZIKV.
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