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 胶质瘤是成人最常见的原发恶性脑瘤，导致超过14,000人死亡 每年在美国。胶质母细胞瘤(GBM)是最常见的胶质瘤类型，总体上 尽管接受了积极的治疗，但存活时间不到21个月。像其他人类癌症一样，基底节细胞瘤已经被激活 一种称为端粒酶的酶，它重建染色体的末端--称为端粒的区域--以 使细胞能够复制永生。事实上，大约90%的GBM病例在 激活端粒酶的TERT基因。不幸的是，到目前为止，直接针对端粒酶活性的努力已经 由于缺乏有效的小分子穿过血脑屏障，表现在靶标上 效果，并显示出对GBMS的有效性和特异性。因此，迫切需要发展安全和 端粒酶靶向治疗肿瘤具有端粒酶活性的基底膜 基因改变。 我们之前使用了嘌呤类似物前药6-硫代-2‘-脱氧鸟苷(6-硫代-DG)，它用于 20世纪70年代的人类临床试验，旨在开发一种快速诱导端粒酶介导的细胞毒DNA的策略 端粒受损。与其抑制端粒酶并允许端粒逐渐变短，6- 硫代-dG被癌细胞摄取并转化为6-硫代-dGTP，然后被掺入新的 合成的端粒重复序列。一旦这些修饰片段在端粒中积累，端粒DNA 损伤迅速产生，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-硫代-DG治疗后，癌细胞被迅速杀死，对正常细胞和组织几乎没有毒性。 重要的是，6-硫代-DG诱导的端粒DNA损伤也增强了抗肿瘤的先天免疫。建房 根据这些数据，我们已经将我们的临床前分析扩展到GBM，并获得了6-硫代-DG交叉的证据 血脑屏障。项目1的总体目标是推动6-硫代-DG进行临床试验 由项目2进行。我们提出以下具体目标：1)表征临床前疗效和 6-硫代-DG单用或与替莫唑胺(TMZ)合用治疗高血压的药效学生物标志物 患者来源的细胞系、PDX和有机模型的扩展面板；2)测试抗肿瘤效果和 6-硫代-DG单独及与TMZ或免疫检查点阻断(ICB)联合应用的炎症潜能 免疫活性小鼠GBM模型的治疗；3)确定细胞毒性和先天炎症 6-硫代-DG在体外胶质瘤组织框架和患者衍生器官中的潜力。这些研究将 确定6-硫代-DG治疗肾小球基底膜的临床前疗效，并确定指导治疗的生物标志物。 包括入选标准在内的临床试验设计。该项目将与拟议的行政部门密切合作 核心、分子生物标志物核心资源和项目2，以实现我们推进6-硫代-DG的共同目标 走向GBM的临床应用。