6-thio-2'-deoxyguanosine in GBM: Pre-clinical Evaluation of Mechanism of action, Efficacy and Biomarker identification

GBM 中的 6-硫代-2-脱氧鸟苷：作用机制、功效和生物标志物鉴定的临床前评估

• 批准号: 10305568
• 负责人: David M. Ashley
• 金额: $ 60.67万
• 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/10305568
• 关键词: Adult; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Cell Death; Cell Line; Cell division; Cells; Cessation of life; Chromosomes; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Colon; Colon Carcinoma; Complex; DNA; DNA Damage; Data; Deoxyguanosine; Dose; Dose-Limiting; Enrollment; Enzymes; Excision; Flow Cytometry; Functional disorder; Gene Activation; Glioblastoma; Glioma; Goals; Guanine; Human; Immunocompetent; Inflammatory; Inflammatory Response; Lung; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Modeling; Mutation; Natural Immunity; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Organoids; Pathologic; Patients; Pre-Clinical Model; Prodrugs; Publishing; RNA-Directed DNA Polymerase; Radiation; Resources; Series; Signal Pathway; Slice; Specificity; Stimulator of Interferon Genes; TERT gene; Telomerase; Telomere Maintenance; Telomere Shortening; Testing; Tissues; Toxic effect; Tumor Immunity; United States; Work; Xenograft procedure; adaptive immune response; aggressive therapy; base; biomarker identification; blood-brain barrier penetration; cancer cell; cell killing; clinical application; cytokine; cytotoxic; deoxyguanosine triphosphate; efficacy testing; immune checkpoint blockade; immunogenic; lung Carcinoma; melanoma; molecular marker; mouse model; mutational status; novel; pharmacodynamic biomarker; pre-clinical; preclinical efficacy; preclinical evaluation; prevent; promoter; purine analog; response biomarker; small molecule; targeted treatment; telomere; temozolomide; therapy resistant; transcriptomics; tumor; tumor microenvironment

PROJECT SUMMARY – Project 1 Gliomas are the most common primary malignant brain tumor in adults and account for over 14,000 deaths annually in the United States. The most common type of glioma, glioblastoma (GBM) has a median overall survival of less than 21 months in spite of aggressive therapy. GBMs, like other human cancers, have activated an enzyme called telomerase that rebuilds the ends of the chromosomes – regions known as telomeres – to enable the cell’s replicative immortality. Indeed, roughly 90% of GBM cases harbor genetic alterations in the TERT gene that activate telomerase. Unfortunately, efforts to directly target telomerase activity to date have been hindered by lack of effective small molecules that cross the blood-brain-barrier, demonstrate on-target effects, and show efficacy and specificity in GBMs. Therefore, there is a critical need to develop safe and efficacious telomerase-targeted therapies for patients with GBM whose tumors harbor telomerase activating genetic alterations. We previously used the purine analog pro-drug 6-thio-2’-deoxyguanosine (6-thio-dG), which was used in human clinical trials in the 1970s, to develop a strategy for rapidly inducing telomerase-mediated cytotoxic DNA damage at telomeres. Rather than inhibiting telomerase and allowing telomeres to get progressively shorter, 6- thio-dG is taken up by cancer cells and converted into 6-thio-dGTP, which is then incorporated into newly synthesized telomeric repeats. Once these modified segments accumulate in the telomeres, telomeric DNA damage rapidly results, ultimately leading to cell death. In pre-clinical models of lung, colon, and melanoma, treatment with 6-thio-dG led to rapid killing of the cancer cells with little toxicity to normal cells and tissues. Importantly, telomeric DNA damage induced by 6-thio-dG also enhanced anti-tumor innate immunity. Building on these data, we have extended our pre-clinical analysis to GBMs and obtained evidence that 6-thio-dG crosses the blood-brain-barrier. The overall objective for Project 1 is to advance 6-thio-dG toward a clinical trial to be conducted by Project 2. We propose the following Specific Aims: 1) Characterize the pre-clinical efficacy and pharmacodynamic biomarkers of 6-thio-dG treatment alone or in combination with Temozolomide (TMZ) in an extended panel of patient-derived cell lines, PDX and organoid models; 2) Test the anti-tumor efficacy and inflammatory potential of 6-thio-dG alone and in combination with TMZ or immune checkpoint blockade (ICB) therapies in immune competent murine models of GBM; and 3) Define cell toxicity and innate inflammatory potential of 6-thio-dG in an ex vivo glioma tissue framework and patient-derived organoids. These studies will determine the pre-clinical efficacy of 6-thio-dG in GBM and confirm biomarkers of efficacy that will guide the design of clinical trials including enrollment criteria. This Project will work closely with the proposed Administrative Core, Molecular Biomarker Core Resource, and Project 2 to achieve our shared goal of advancing 6-thio-dG toward clinical application in GBM.

项目摘要 - 项目1 神经胶质瘤是成人最常见的主要原发性恶性脑肿瘤，占14,000多人死亡 每年在美国。神经胶质瘤最常见类型的胶质母细胞瘤（GBM）的总体中位数 尽管进行了积极的治疗，但生存率少于21个月。与其他人类癌症一样，GBM也已激活 一种称为端粒酶的酶，将染色体的末端（称为端粒区域）重建为 启用细胞的复制永生。实际上，大约90％的GBM病例具有遗传改变 激活端粒酶的TERT基因。不幸的是，迄今为止直接针对端粒酶活动的努力 由于缺乏跨越血脑屏障的有效小分子，他受到阻碍 效果并显示GBMS的效率和特异性。因此，迫切需要安全和 GBM患者的有效端粒酶靶向疗法，其肿瘤携带端粒酶激活 遗传改变。 我们以前使用了Purine Analog Pro-pro-drug 6- thio-2'-脱氧鸟苷（6- thio-dg） 1970年代的人类临床试验制定了一种快速诱导端粒酶介导的细胞毒性DNA的策略 端粒的损坏。而不是抑制端粒并允许端粒逐渐变短，6- THIO-DG被癌细胞吸收并转化为6- thio-DGTP，然后将其纳入新的 合成的远程重复序列。一旦这些修饰的片段积聚在端粒中，远程射精DNA 损害迅速导致，最终导致细胞死亡。在肺，结肠和黑色素瘤的临床前模型中 用6- thio-DG治疗导致对正常细胞和组织毒性的癌细胞迅速杀死。 重要的是，由6- thio-DG诱导的远程诊断DNA损伤也增强了抗肿瘤的先天免疫力。建筑 在这些数据上，我们已将临床前分析扩展到GBM，并获得了6-Thio-DG横断的证据 血脑屏障。项目1的总体目标是将6- thio-DG推向临床试验 由项目2进行。我们提出以下具体目的：1）表征临床前效率和 单独或与替莫唑胺（TMZ）合并的6- thio-DG治疗的药物学生物标志物 扩展的患者衍生细胞系，PDX和类器官模型的面板； 2）测试抗肿瘤效率和 单独使用6-Thio-DG并与TMZ或免疫检查点阻滞（ICB）结合使用的炎症潜力（ICB） GBM的免疫能力鼠模型中的疗法； 3）定义细胞毒性和先天炎症 在离体神经胶质瘤组织框架和患者衍生的类器官中，6- thio-dg的潜力。这些研究会 确定6-THIO-DG在GBM中的临床前效率，并确认效率的生物标志物，以指导 包括入学标准在内的临床试验的设计。该项目将与拟议的管理紧密合作 核心，分子生物标志物核心资源和项目2，以实现我们提高6-Thio-DG的共同目标 在GBM中临床应用。