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.

项目概述-整体