6-thio-2'-deoxyguanosine: A Novel Immunogenic Telomerase-Mediated Therapy in Glioblastoma - A Duke and UTSW Collaboration

6-硫代-2-脱氧鸟苷：一种新型免疫原性端粒酶介导的胶质母细胞瘤疗法 - 杜克大学和 UTSW 合作

• 批准号: 10488237
• 负责人: David M. Ashley
• 金额: $ 84.32万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-13 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488237
• 关键词: Address; Adult; Adult Glioblastoma; Animals; Basic Science; Bioinformatics; Biological; Biological Markers; Biological Models; Biotechnology; Brain; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cancer Etiology; Clinical; Clinical Data; Clinical Research; Clinical Treatment; Clinical Trials; Collaborations; Communication; Cross-Priming; DNA; DNA Damage; Data; Decision Making; Dendritic Cells; Deoxyguanosine; Development; Diagnosis; Doctor of Philosophy; Drug Targeting; Eligibility Determination; Ensure; Excision; Experimental Designs; Future; Glioblastoma; Human; Immune; Immunologic Adjuvants; Immunotherapeutic agent; Infrastructure; Institution; Interferons; Lead; Leadership; Letters; Link; Malignant - descriptor; Mediating; Medical center; Modeling; Monitor; Office of Administrative Management; Operative Surgical Procedures; Organoids; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase 0 Clinical Trial; Pilot Projects; Population Heterogeneity; Primary Brain Neoplasms; Publishing; Reporting; Research; Resistance; Resources; Safety; Sampling; Scientist; Slice; Solid Neoplasm; Somatic Cell; Stratification; Telomerase; Texas; Therapeutic; Time; Tissues; Toxic effect; Translational Research; Tumor Escape; Universities; Work; adaptive immune response; anti-tumor immune response; biobank; blood-brain barrier penetration; chemotherapy; childhood cancer mortality; clinical translation; design; drug action; effectiveness study; fighting; immune checkpoint blockade; immunogenic; in vivo; innovation; mouse model; neuro-oncology; novel; novel strategies; operation; overexpression; patient population; pharmacodynamic biomarker; pre-clinical; preclinical development; preclinical efficacy; response; response biomarker; screening; success; telomere; temozolomide; translational physician; translational scientist; tumor; young adult

PROJECT SUMMARY – Overall Glioblastoma (GBM) is one of the most frequent causes of cancer death in children and young adults and is also the most common malignant primary brain tumor in adults. Moreover, current therapy is incapacitating and is limited by non-specific toxicity. Despite hundreds of clinical trials, few agents have been approved for clinical use, and the tumors addressed in this application remain uniformly lethal. This Glioblastoma Trials Network (GTN) application will address this problem through a collaborative group of translational physician-scientists at Duke University and the University of Texas Southwestern Medical Center proposing a novel approach for treatment of GBM using a telomere-targeting drug, 6-thio-2′-deoxyguanosine (6-thio-dG). Telomerase is an attractive target for anti-GBM therapy as it is over-expressed in the vast majority of GBM. Additionally, our pre-clinical data shows that treatment of tumor bearing animals with 6-thio-dG leads to tumor regression through the dual activity of both DNA damage and innate and adaptive immune responses. Most recently through our collaborative effort we have already commenced studies in GBM with a developmental plan ideally suited to the GTN. Project 1 will use a variety of model systems to characterize how 6-thio-dG leads to tumor regression in GBM examining both DNA damage and innate and adaptive immune responses, and will inform the design of the 0 trial proposed in Project 2. Project 2 will examine mechanisms of tumor escape to 6- thio-dG treatment in mouse models of GBM, conduct a phase 0 clinical trial of 6-thio-dG treatment in GBM, and, informed by Project 1 and the Biomarker, Bioinformatics and Biorepository Core, utilize a number of screening, stratification and pharmacodynamic biomarkers to guide decision-making. The proposed Biomarker, Bioinformatics and Biorepository Core will support accurate and robust diagnoses and pharmaco-dynamic (PD) assessments of 6-thio-dG therapy. It will also provide a number of utilities including sample acquisition and distribution, statistical leadership and expertise in the design, conduct, analysis and reporting of biomarker studies. The Core will acquire high-quality primary human samples linked with clinical data in Project 2 and develop and validate innovative analytical and immune profiling strategies to ensure rigorous experimental design and conduct is consistent across the Projects. The Administrative Core will provide organizational leadership, fiscal management administrative support, and will monitor research progress, oversee data operations, ensure compliance and quality, and facilitate communication and collaboration for both Projects. This GTN proposal benefits from strong leadership, an established collaboration, and the large and diverse population of patients with glioblastoma who are seen at Duke and UTSW. The proposed work successfully completed would lead to initial studies of effectiveness in patients with GBM, potentially adding an important new approach to fight GBM.

项目概要——总体 胶质母细胞瘤 (GBM) 是儿童和年轻人癌症死亡的最常见原因之一，也是 成人中最常见的恶性原发性脑肿瘤此外，目前的治疗方法会导致患者丧失能力。 尽管有数百项临床试验，但很少有药物被批准用于临床。 使用，并且本申请中涉及的肿瘤仍然是一致致命的。 （GTN）应用程序将通过转化医师科学家合作小组解决这个问题 杜克大学和德克萨斯大学西南医学中心提出了一种新方法 使用端粒靶向药物 6-thio-2'-deoxyguanosine (6-thio-dG) 治疗 GBM。 端粒酶是抗 GBM 治疗的一个有吸引力的靶点，因为它在绝大多数细胞中过度表达。 此外，我们的临床前数据表明，用 6-thio-dG 治疗荷瘤动物会导致 通过 DNA 损伤以及先天性和适应性免疫反应的双重活性来消退肿瘤。 最近，通过我们的合作努力，我们已经开始对 GBM 进行发育性研究 非常适合 GTN 的计划 项目 1 将使用各种模型系统来表征 6-thio-dG 如何引导。 GBM 中的肿瘤消退检查 DNA 损伤以及先天性和适应性免疫反应，并将 告知项目 2 中提出的 0 试验的设计。项目 2 将检查肿瘤逃逸至 6- 的机制 在 GBM 小鼠模型中进行 thio-dG 治疗，进行 GBM 6-thio-dG 治疗的 0 期临床试验，以及 根据项目 1 和生物标记、生物信息学和生物样本库核心，利用了许多 筛选、分层和药效生物标志物以指导决策。 生物信息学和生物库核心将支持准确、稳健的诊断和药效学 它还将提供许多实用程序，包括样品采集和 6-thio-dG 疗法的 (PD) 评估。 生物标志物设计、实施、分析和报告方面的分布、统计领导力和专业知识 核心将获取与项目 2 和 2 中的临床数据相关的高质量原始人类样本。 开发和验证创新的分析和免疫分析策略，以确保严格的实验 整个项目的设计和行为是一致的。管理核心将提供组织。 领导、财政管理行政支持，并将监测研究进展、监督数据 运营，确保合规性和质量，并促进两个项目的沟通和协作。 GTN 提案受益于强有力的领导、既定的合作以及庞大且多样化的人口 在杜克大学和 UTSW 就诊的胶质母细胞瘤患者成功完成了拟议的工作。 将导致对 GBM 患者有效性的初步研究，可能会增加一种重要的新方法 对抗 GBM。