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

项目总结--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脑瘤。此外，目前的治疗方法使人丧失能力，而且 受到非特异性毒性的限制。尽管进行了数百次临床试验，但很少有药物被批准用于临床 使用，本申请中涉及的肿瘤仍然是一致致命的。这个胶质母细胞瘤试验网络 (GTN)应用程序将通过一个由翻译医生和科学家组成的协作小组来解决这一问题，网址为 杜克大学和德克萨斯大学西南医学中心提出了一种新的方法 使用端粒靶向药物6-硫代-2‘-脱氧鸟苷(6-硫代-DG)治疗基底膜。 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 GBM。此外，我们的临床前数据显示，用6-硫代-DG治疗荷瘤动物会导致 通过DNA损伤和先天和获得性免疫反应的双重作用使肿瘤退变。 最近，通过我们的合作努力，我们已经开始了对GBM的研究，并开发了 最适合GTN的计划。项目1将使用各种模型系统来表征6-硫代-DG如何领先 在GBM中检测DNA损伤和先天和获得性免疫反应的肿瘤消退，并将 告知项目2中建议的0试验的设计。项目2将检查肿瘤逃逸到6- 硫代-DG治疗小鼠基底膜模型，进行6-硫代-DG治疗基底膜的0期临床试验， 由项目1和生物标记、生物信息学和生物信息库核心提供信息，利用许多 用于指导决策的筛选、分层和药效学生物标志物。拟议的Biomarker， 生物信息学和生物信息库核心将支持准确和强大的诊断和药物动力学 (Pd)6-硫代-DG治疗的评估。它还将提供一些实用程序，包括样本采集和 在生物标志物的设计、实施、分析和报告方面的分布、统计领导和专业知识 学习。核心将获取与项目2和临床数据相关联的高质量初级人体样本 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 整个项目的设计和实施是一致的。行政核心将提供组织 领导，财政管理，行政支持，并将监测研究进展，监督数据 业务，确保合规和质量，促进两个项目的沟通和协作。这 GTN计划受益于强大的领导力、成熟的协作以及庞大而多样化的人群 在杜克大学和休斯顿大学就诊的胶质母细胞瘤患者的比例。拟议的工作圆满完成 将导致对GBM患者有效性的初步研究，潜在地增加了一种重要的新方法 来对抗GBM。

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.