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.

项目摘要 - 总体 胶质母细胞瘤（GBM）是儿童和年轻人最常见的癌症死亡原因之一，也是 成人最常见的恶性原发性脑肿瘤。此外，当前的疗法是无能力的，并且是 受非特异性毒性的限制。尽管有数百次临床试验，但很少有代理被批准用于临床 使用，此应用中解决的肿瘤仍然均匀致死。这个胶质母细胞瘤试验网络 （GTN）应用程序将通过翻译的物理科学家的协作组解决此问题 杜克大学和德克萨斯大学西南医学中心提出了一种新颖的方法 使用端粒靶向药物，6- thio-2'-脱氧鸟苷（6- thio-dg）处理GBM。 端粒酶是抗GBM治疗的有吸引力的靶标，因为它在绝大多数 GBM。另外，我们的临床前数据表明，用6- thio-dg的肿瘤轴承的治疗导致 通过DNA损伤以及先天和适应性免疫调查的双重活性的肿瘤回归。 最近，通过我们的协作努力，我们已经开始在GBM上进行发展 理想的计划适合GTN。项目1将使用各种模型系统来表征6-Thio-DG的引线 GBM中的肿瘤回归，检查DNA损伤以及先天和适应性免疫回报，并将 告知项目2中提出的0个试验的设计。项目2将检查肿瘤的机制逃逸到6-- GBM小鼠模型中的硫-DG处理，进行了0阶段的临床试验，对GBM中的6- thio-DG处理以及，以及 由项目1和生物标志物，生物信息学和生物座席核心告知，利用了许多 筛查，分层和药效生物标志物指导决策。拟议的生物标志物， 生物信息学和生物座位核心将支持准确，稳健的诊断和药物动态 （PD）6- tHio-DG疗法的评估。它还将提供许多公用事业，包括样本采集和 生物标志物的设计，行为，分析和报告的分销，统计领导和专业知识 研究。核心将获取与项目2中的临床数据相关的高质量主要人类样本， 制定和验证创新的分析和免疫分析策略，以确保严格的实验 设计和行为在整个项目中都是一致的。行政核心将提供组织 领导力，财政管理行政支持，并将监控研究进度，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。这 GTN提案受益于强大的领导，既定的合作以及大型和潜水员的人口 在杜克大学和UTSW中看到的胶质母细胞瘤患者。拟议的工作成功完成 将导致对GBM患者有效性的初步研究，并可能添加一种重要的新方法 与GBM战斗。