The long-term objective of this R21 proposal is developing the non-toxic plant product resveratrol as an agent to specifically inhibit glioma cell dispersal, for future use alongside current surgical, radiation, and chemotherapeutic strategies. Malignant gliomas such as glioblastoma multiforme (GBM) are the most common and deadly primary brain neoplasms, and even with aggressive interventions average survival remains less than 2 years after diagnosis. Extensive dispersal of therapy-resistant glioma cells into surrounding brain prevents efficient treatment, resulting in tumor recurrence immediately adjacent to the resection cavity in greater than 90% of cases. Therefore, new treatments or approaches specifically inhibiting invasive properties of glioma cells are highly desirable, and ideal candidates in this respect would be non-toxic so that the toxic load of the treatment regimen remains manageable. The natural product resveratrol satisfies these needs, causing virtually no side effects when administered in vivo and demonstrating wide-ranging anti-oncogenic effects, including invasion inhibition, on diverse cancer types. Our collaborators have demonstrated resveratrol's ability to inhibit infiltration of highly aggressive melanoma in a mouse model by disrupting AKT signaling. In brain tumors, oncogenic AKT is critical to continued cell growth, survival, and invasion. Additionally, we have developed novel resveratrol formulations that can increase serum levels of unmodified resveratrol 10-fold and can be delivered intratumorally as well as orally. We hypothesize that resveratrol can inhibit dispersal of highly aggressive glioma cells by disrupting AKT. To test this hypothesis, we will use our novel glioma initiating cell (GIC) model, established through sphere culture of 5 independent human GBMs. These GICs are highly invasive when implanted into a mouse orthotopic model, unlike historical glioma cell lines, and our multiple independent lines better represent the genetic diversity of human GBM compared to single transgenic mouse models. Our preliminary data already demonstrate in vitro resveratrol-mediated inhibition of GIC invasion in a basement membrane assay.
In specific aim 1, we will determine the ability of resveratrol to inhibit glioma invasion ad dispersal of our multiple genetically diverse GIC lines, testing novel formulations and delivery of resveratrol as well. We will use basement membrane invasion assays in vitro and our orthotopic mouse model in vivo to test resveratrol's anti-invasive properties across physiologically relevant doses.
In specific aim 2, we will elucidate the role of resveratrol-modulated AKT on glioma infiltration. We will first analyze changes in activated and total AKT upon resveratrol administration in vitro and in vivo. Secondly, we will use over-expression and dominant-negative (knock-out) AKT strategies in our GIC lines and analyze effects on resveratrol responsiveness. We believe that successful completion of these aims will lay the foundation for follow-up clinical testing of the non-toxic natural agent, resveratrol, combined with current GBM therapies to improve patient survival and quality of life by inhibiting tumor invasion into functional brain.

Public Health Relevance

Gliomas arise from the most abundant brain glial cells, and are the most common and deadly primary brain cancers. Extensive dispersal and invasion of glioma cells into surrounding brain is a current major roadblock to efficient treatments. Non-toxic agents that supplement current therapies are highly desirable to specifically inhibit cancer cell invasion into adjacent functiona brain, minimize side effects and improve treatment efficacy. In this R21 application, we plan to test the ability of the non-toxic, natural plant product resveratrol to block glioma cell dispersal with the future goal of translating resveratrol to the clinic as a non-toxic, effective supplement o current treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Chemo/Dietary Prevention Study Section (CDP)
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Fu, Yali
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University of Wisconsin Madison
Schools of Medicine
United States
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Clark, Paul A; Bhattacharya, Saswati; Elmayan, Ardem et al. (2017) Resveratrol targeting of AKT and p53 in glioblastoma and glioblastoma stem-like cells to suppress growth and infiltration. J Neurosurg 126:1448-1460
Swanson, Kyle I; Clark, Paul A; Zhang, Ray R et al. (2015) Fluorescent cancer-selective alkylphosphocholine analogs for intraoperative glioma detection. Neurosurgery 76:115-23; discussion 123-4
Brower, Jeffrey V; Clark, Paul A; Lyon, Will et al. (2014) MicroRNAs in cancer: glioblastoma and glioblastoma cancer stem cells. Neurochem Int 77:68-77