In this proposal we will attempt to further define the mechanistic pathways involved in enhancing tumor immunity using epigenetic agents and improved strategies for enhancing their effectiveness. The long-term goal is to transfer this technology to clinical application.
Our specific aims are to determine: 1) the role of enhanced antigen presentation by histone deacetylase inhibitor (HDACi) treated tumor cells in a B16 melanoma vaccine model; 2) the contribution of NK cells to immunity in the epigenetic model; 3) the efficacy of these models in combinations of HDACi with hyperthermia and radiation; 4) the effects of systemic HDACi therapy in combination with other modalities. An additional major aim is to characterize the role of Dicer and microRNA in immune gene regulation. Our studies have identified miRNAs which target several miRNA machinery components including Dicer. We also defined several stresses that downregulate Dicer (ROS, anoxia, dsRNA) and will determine the pathways by which expression of Dicer is regulated. MiRNAs and siRNAs targeting Dicer will be employed to de-repress silenced genes and to determine whether this enhances immune gene expression in combination with HDACi which are currently in clinical trials. The proposed studies are pre-clinical and exploit the B16 melanoma, colon26, as well as the SCC head and neck cancer models. Our studies will employ in vitro immunological assays, standard molecular biology techniques and microarrays for characterization of gene and miRNA expression. Fresh H&N tissue, removed at surgery, will be studied in preparation for a proposed clinical trial.
This application focuses on pre-clinical and mechanistic studies of a new class of agents (histone deacetylase inhibitors) now currently being evaluated in clinical trials. These studies address a novel mechanism by which these agents may improve cancer therapy with low toxicity (compared to standard chemotherapeutics). ? ? ?
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| Magner, William J; Weinstock-Guttman, Bianca; Rho, Mina et al. (2016) Dicer and microRNA expression in multiple sclerosis and response to interferon therapy. J Neuroimmunol 292:68-78 |
| Hoffend, Nicholas C; Magner, William J; Tomasi, Thomas B (2016) The modulation of Dicer regulates tumor immunogenicity in melanoma. Oncotarget 7:47663-47673 |
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| Oshlag, Julian Z; Devasthanam, Anand S; Tomasi, Thomas B (2013) Mild hyperthermia enhances the expression and induces oscillations in the Dicer protein. Int J Hyperthermia 29:51-61 |
| Tomasi, Thomas B; Magner, William J; Wiesen, Jennifer L et al. (2010) MHC class II regulation by epigenetic agents and microRNAs. Immunol Res 46:45-58 |
| Wiesen, Jennifer L; Tomasi, Thomas B (2009) Dicer is regulated by cellular stresses and interferons. Mol Immunol 46:1222-8 |
| Gregorie, Christopher J; Wiesen, Jennifer L; Magner, William J et al. (2009) Restoration of immune response gene induction in trophoblast tumor cells associated with cellular senescence. J Reprod Immunol 81:25-33 |
| Asirvatham, Ananthi J; Magner, William J; Tomasi, Thomas B (2009) miRNA regulation of cytokine genes. Cytokine 45:58-69 |
