Epigenetic Regulation of Immune Genes in Cancer Treatment and Vaccine Protocols

癌症治疗和疫苗方案中免疫基因的表观遗传调控

• 批准号: 7528791
• 负责人: THOMAS B TOMASI
• 金额: $ 32.75万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7528791
• 关键词: Address; Affect; Anoxia; Antigen Presentation; Attention; Bioinformatics; Biological Assay; Cancer Model; Cancer Vaccines; Cells; Chromatin; Class; Clinical Trials; Collaborations; Combined Modality Therapy; Data; Deacetylase; Disease; Dose; Double-Stranded RNA; Effectiveness; Epigenetic Process; Event; Fever; Gene Expression; Gene Expression Regulation; Gene Silencing; Gene Targeting; Generations; Genes; Goals; Grant; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Histone Deacetylase Inhibitor; Human; Immune; Immune response; Immunity; Immunization; Immunologics; In Vitro; Interferon Type I; Ligands; MAP Kinase Gene; Mediating; Melanoma Cell; Melanoma Vaccine; MicroRNAs; Microfluidics; Modality; Modeling; Molecular; Molecular Biology Techniques; Mus; Natural Killer Cells; Operative Surgical Procedures; Paper; Pathway interactions; Preparation; Prevention; Protocols documentation; Public Health; Publishing; Radiation; Regulation; Research Personnel; Role; Route; Small Interfering RNA; Squamous cell carcinoma; Standards of Weights and Measures; Stress; Techniques; Technology Transfer; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; Tumor Immunity; Vaccines; Work; base; biological adaptation to stress; cancer therapy; clinical application; clinically relevant; cytokine; dosage; human DICER1 protein; hyperthermia treatment; improved; inhibitor/antagonist; irradiation; melanoma; neoplastic cell; novel; pre-clinical; preclinical study; protein expression; research study; response; statistics; tumor; tumor growth; vaccine efficacy

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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).

描述（由申请人提供）：在本提案中，我们将尝试进一步定义使用表观遗传剂增强肿瘤免疫的机制途径以及增强其有效性的改进策略。长期目标是将这项技术转化为临床应用。我们的具体目标是确定：1​​) 在 B16 黑色素瘤疫苗模型中，组蛋白脱乙酰酶抑制剂 (HDACi) 处理的肿瘤细胞增强抗原呈递的作用； 2）表观遗传模型中NK细胞对免疫的贡献； 3) 这些模型结合 HDACi 与热疗和放射的疗效； 4) 全身HDACi治疗与其他方式联合的效果。另一个主要目标是表征 Dicer 和 microRNA 在免疫基因调节中的作用。我们的研究已经确定了针对包括 Dicer 在内的多种 miRNA 机械组件的 miRNA。我们还定义了几种下调 Dicer 的应激（ROS、缺氧、dsRNA），并将确定 Dicer 表达的调节途径。针对 Dicer 的 MiRNA 和 siRNA 将用于去抑制沉默基因，并确定这是否与目前正在进行临床试验的 HDACi 结合增强免疫基因表达。拟议的研究是临床前研究，利用 B16 黑色素瘤、结肠癌以及 SCC 头颈癌模型。我们的研究将采用体外免疫学测定、标准分子生物学技术和微阵列来表征基因和 miRNA 表达。手术中取出的新鲜 H&N 组织将进行研究，为拟议的临床试验做准备。公共健康相关性：本申请重点关注目前正在临床试验中评估的一类新型药物（组蛋白脱乙酰酶抑制剂）的临床前和机制研究。这些研究提出了一种新机制，通过该机制，这些药物可以以低毒性改善癌症治疗（与标准化疗药物相比）。