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: 10488242
• 负责人: David M. Ashley
• 金额: $ 52.22万
• 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/10488242
• 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原发性恶性脑肿瘤，导致 14,000 多人死亡 在美国，胶质母细胞瘤（GBM）是最常见的类型，其总体中位数为每年。 尽管像其他人类癌症一样，GBM 已被激活，但其生存期仍不足 21 个月。 一种称为端粒酶的酶，可以重建染色体末端（称为端粒的区域），以 事实上，大约 90% 的 GBM 病例都存在基因改变。 不幸的是，迄今为止，直接靶向端粒酶活性的努力还不够。 由于缺乏有效的穿过血脑屏障的小分子而受到阻碍，证明其达到目标 因此，迫切需要开发安全且有效的药物。 对于肿瘤具有端粒酶激活的 GBM 患者有效的端粒酶靶向治疗 基因改变。 我们之前使用过嘌呤类似物前药 6-thio-2'-deoxyguanosine (6-thio-dG)，它被用于 20世纪70年代的人体临床试验，开发一种快速诱导端粒酶介导的细胞毒性DNA的策略 端粒受损，而不是抑制端粒并让端粒逐渐变短，6- thio-dG 被癌细胞吸收并转化为 6-thio-dGTP，然后掺入新的 6-thio-dGTP 中。 一旦这些修饰片段在端粒中积累，端粒DNA就会被合成。 在肺、结肠和黑色素瘤的临床前模型中，会产生快速损伤，最终导致细胞死亡。 6-thio-dG 治疗可快速杀死癌细胞，而对正常细胞和组织的毒性很小。 重要的是，6-thio-dG 诱导的端粒 DNA 损伤也增强了抗肿瘤先天免疫的建立。 根据这些数据，我们将临床前分析扩展到 GBM，并获得了 6-thio-dG 交叉的证据 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标：1）表征临床前疗效和 单独或与替莫唑胺 (TMZ) 联合治疗的 6-硫代-dG 治疗的药效生物标志物 扩展的患者来源细胞系、PDX 和类器官模型；2) 测试抗肿瘤功效和 单独使用 6-硫代-dG 以及与 TMZ 或免疫检查点阻断 (ICB) 联合使用的炎症潜力 GBM 免疫活性小鼠模型中的治疗；3) 定义细胞毒性和先天性炎症 这些研究将探讨 6-thio-dG 在离体神经胶质瘤组织框架和患者来源的类器官中的潜力。 确定 6-thio-dG 在 GBM 中的临床前疗效，并确认疗效的生物标志物，以指导 临床试验的设计，包括招募标准，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-thio-dG 的共同目标 GBM 的临床应用。