6-thio-2'-deoxyguanosine in GBM: Evaluation of Pharmaco-dynamics, Effects of Prior Standard of Care and A Human Phase 0 Study

GBM 中的 6-硫代-2-脱氧鸟苷：药效学评估、先前护理标准的影响和人类 0 期研究

• 批准号: 10488244
• 负责人: Mustafa Khasraw
• 金额: $ 14.57万
• 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/10488244
• 关键词: Adult; Adult Glioblastoma; Aftercare; Animals; Biological; Biological Markers; Biology; Blood - brain barrier anatomy; Brain Neoplasms; Cell Death; Cells; Clinical Data; Clinical Trials; Collaborations; Cyclic GMP; DNA Damage; Deoxyguanosine; Dependence; Evaluation; Event; Evolution; Failure; Gamma-H2AX; Genes; Glioblastoma; Gliomagenesis; Goals; Harvest; Human; Immune; Immune response; Immune signaling; Immunity; Immunosuppression; Immunotherapy; Implant; Induced Mutation; Infrastructure; Interferons; Malignant Neoplasms; Measures; Mediating; Methods; Modality; Modeling; Molecular; Monitor; Mus; Mutation; Mutation Detection; Newly Diagnosed; Operative Surgical Procedures; Patients; Pattern; Pharmacodynamics; Phase; Phase 0 Clinical Trial; Phase 0 Study; Phase 0 Trial; Pre-Clinical Model; Prodrugs; Radiation; Recurrence; Relapse; Resistance; Role; Seminal; Signal Transduction; Subgroup; Telomerase; Testing; Therapeutic; Time; Tissues; Toxic effect; Tumor Tissue; Tumor-infiltrating immune cells; Up-Regulation; Work; anti-tumor immune response; base; checkpoint inhibition; cohort; cytotoxicity; design; early phase clinical trial; efficacy evaluation; experience; experimental study; immune activation; immunogenic; improved; in vivo; innate immune sensing; mutant; neoplasm immunotherapy; novel; novel therapeutics; patient derived xenograft model; patient population; pharmacodynamic biomarker; pre-clinical; preclinical development; preclinical study; predictive marker; pressure; primary endpoint; promoter; purine analog; response; response biomarker; standard of care; targeted agent; telomere; temozolomide; transcriptome sequencing; treatment response; tumor; tumor heterogeneity

PROJECT SUMMARY – Project 2 Glioblastoma (GBM) remains uniformly lethal, with an overall survival of <21 months despite standard of care therapies. Immunotherapy has remarkable efficacy in many cancers, but has been less successful in GBM due in part to the tumor’s immunosuppressive effects and high levels of intratumoral heterogeneity. The Duke/UT Southwestern Glioblastoma Therapeutics Network (GTN) team will complete pre-clinical development of a novel treatment for patients with glioblastoma (GBM) and investigate the biologic activity of this agent in an early-phase clinical trial. Project 2 will contribute to this goal by investigating biomarkers of response to the telomerase- targeted agent 6-thio-dG in pre-clinical models and by conducting a Phase 0 clinical trial to examine these biomarkers in humans. 6-thio-dG is a blood brain barrier (BBB)-penetrant purine analog pro-drug that is preferentially incorporated into newly synthesized telomeres under the control of telomerase. Incorporation of 6- thio-dG into telomeres induces DNA damage and activates innate immune signaling, resulting in cell death. Because roughly 90% of GBM express telomerase resulting from early and highly clonal TERT-promoter mutations, 6-thio-dG represents an exciting mechanism to overcome tumor heterogeneity and activate anti-tumor immune responses. Although we have shown that treatment with 6-thio-dG induces telomeric DNA damage and elicits immune-mediated cytotoxicity in telomerase-positive cells, the optimal time-point for measuring 6-thio-dG- induced DNA damage and innate immune activation as pharmacodynamic (PD) endpoints is unknown and will be rigorously determined using patient-derived xenograft models (Aim 1). Additionally, most GBM patients receive first-line treatment with temozolomide (TMZ), which can induce hypermutation and loss of telomerase activity at recurrence. We will therefore evaluate the efficacy of 6-thio-dG following prior TMZ treatment and identify mechanisms of therapy resistance in vivo (Aim 1). Based on experiments conducted in Aim 1 and in Project 1, we will establish preliminary biomarkers of sensitivity and response to 6-thio-dG treatment in a Phase 0 window-of-opportunity trial in adults with newly diagnosed, telomerase-positive GBM (Aim 2). Following a 2- day pre-surgical course of 6-thio-dG, we will examine GBM tissues for detectable increases in DNA damage (primary endpoint) and activation of immune responses. These studies will enable the design and conduct of a Phase 0 trial of 6-thio-dG, identify patient populations likeliest to benefit from therapy, and assess biomarkers of sensitivity and response to 6-thio-dG among newly diagnosed patients with telomerase-positive GBM. The GBM clinical trials infrastructures of Duke and UTSW, which treat a diverse patient population representing ~10% of all U.S. patients with GBM, is an excellent setting for this trial. Project 2 thus contributes to this GTN U19’s overall goal and to the NCI’s goal to develop novel therapies to improve treatment for adults with GBM.

项目摘要 - 项目2 胶质母细胞瘤（GBM）保持均匀致命，总体生存率<21个月目的地护理标准 疗法。免疫疗法在许多癌症中具有出色的效率 部分是肿瘤的免疫抑制作用和高水平的肿瘤内异质性。公爵/UT 西南胶质母细胞瘤治疗学网络（GTN）团队将完成小说的临床前发展 胶质母细胞瘤（GBM）患者的治疗，并研究该药物在早期期间的生物学活性 临床试验。项目2将通过调查对遥测酶的反应的生物标志物来为这一目标做出贡献。 靶向剂6- thio-dg在临床前模型中，并通过进行0期临床试验来检查这些试验 人类的生物标志物。 6- thio-dg是血脑屏障（BBB） - perentant pureine purine模拟pro-pro-pro-pro-pro-pro-pro-te 在端粒酶控制下优先掺入新合成的端粒中。掺入6- 将硫代DG进入端粒会诱导DNA损伤并激活先天免疫信号，从而导致细胞死亡。 因为大约90％的GBM Express端粒酶是由早期和高度克隆的促启动子产生的 突变，6-THIO-DG代表了克服肿瘤异质性并激活抗肿瘤的令人兴奋的机制 免疫反应。尽管我们已经表明，用6- thio-dg进行治疗会诱导远程诊断DNA损伤和 引起端粒酶阳性细胞中免疫介导的细胞毒性，这是测量6- thio-dg-的最佳时间点 诱导的DNA损伤和先天免疫激活，因为药效学（PD）端点是未知的，并且将会 使用患者衍生的Xenographic模型严格确定（AIM 1）。此外，大多数GBM患者 接受替莫唑胺（TMZ）的一线治疗，这可以诱导端粒酶的过度成分和丧失 复发时的活动。因此，我们将在先前的TMZ治疗后评估6- thio-dg的效率和 确定体内治疗耐药性的机制（AIM 1）。基于在AIM 1和In中进行的实验 项目1，我们将在一个阶段建立敏感性和对6- thio-dg处理的敏感性和反应的初步生物标志物 0新诊断为端粒酶阳性GBM的成年人中的大型运动窗口试验（AIM 2）。跟随2- 术前的术前6-thio-dg，我们将检查GBM组织是否可检测到DNA损伤的增加 （主要终点）和免疫反应的激活。这些研究将使设计和行为 6- thio-dg的0阶段试验，确定患者人群受益于治疗，并评估生物标志物 在新诊断的端粒酶阳性GBM患者中，敏感性和对6- thio-DG的反应。 GBM 公爵和UTSW的临床试验基础设施，这些基础设施治疗约有约10％的患者人群 所有具有GBM的美国患者，都是该试验的绝佳环境。项目2因此有助于该GTN U19的整体 目标和NCI的目标是开发新型疗法，以改善GBM成年人的治疗方法。