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.

项目总结-项目一