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

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，目前的治疗是失能的， 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，并且本申请中所述的肿瘤保持一致的致死性。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-科学家组成的合作小组来解决这个问题， 杜克大学和德克萨斯大学西南医学中心提出了一种新的方法， 使用端粒靶向药物6-硫代-2 ′-脱氧鸟苷（6-thio-dG）治疗GBM。 端粒酶是抗GBM治疗的有吸引力的靶点，因为它在绝大多数肿瘤中过表达。 GBM。此外，我们的临床前数据显示，用6-硫代-dG治疗荷瘤动物导致肿瘤细胞增殖。 通过DNA损伤和先天性和适应性免疫应答的双重活性，肿瘤消退。 最近，通过我们的合作努力，我们已经开始了GBM的研究， 非常适合GTN的计划。项目1将使用各种模型系统来表征6-硫代-dG如何导致 在GBM中检查DNA损伤以及先天性和适应性免疫反应的肿瘤消退， 通知项目2中提出的0试验的设计。项目2将研究肿瘤逃逸的机制， 在GBM的小鼠模型中进行6-硫代-dG治疗，在GBM中进行6-硫代-dG治疗的0期临床试验，以及， 由项目1和生物标志物，生物信息学和生物储存核心，利用一些 筛选、分层和药效学生物标志物以指导决策。提出的生物标志物， 生物信息学和生物库核心将支持准确和可靠的诊断和药效学 (PD)6-硫代-dG疗法的评估。它还将提供一些实用程序，包括样本采集和 生物标志物设计、实施、分析和报告方面的分布、统计领导和专业知识 问题研究核心将获得与项目2中的临床数据相关的高质量原始人体样本， 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 设计和实施在各项目中保持一致。行政核心将提供组织 领导，财政管理和行政支持，并将监测研究进展，监督数据 确保合规性和质量，促进两个项目的沟通和协作。这 GTN提案受益于强有力的领导、已建立的合作以及庞大而多样化的人口 在杜克和UTSW的胶质母细胞瘤患者中。拟议工作顺利完成 将导致对GBM患者有效性的初步研究，可能增加一种重要的新方法 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.