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: 10305569
• 负责人: Mustafa Khasraw
• 金额: $ 10.67万
• 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/10305569
• 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; cohort; cytotoxicity; design; early phase clinical trial; efficacy evaluation; experience; experimental study; immune activation; immune checkpoint; 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.

项目概要-项目2 胶质母细胞瘤（GBM）仍然是一致致命的，尽管有标准治疗，总生存期<21个月 治疗免疫疗法在许多癌症中具有显著的疗效，但由于免疫疗法在GBM中的效果不太好， 部分原因是肿瘤的免疫抑制作用和高水平的瘤内异质性。杜克/UT 西南胶质母细胞瘤治疗网络（GTN）团队将完成一种新的临床前开发 治疗胶质母细胞瘤（GBM）患者，并研究该药物在早期阶段的生物活性 临床试验项目2将通过研究对端粒酶反应的生物标志物来促进这一目标， 靶向剂6-硫代-dG在临床前模型中的应用，并通过进行0期临床试验来检查这些 生物标志物。6-硫代-dG是血脑屏障（BBB）渗透嘌呤类似物前药， 在端粒酶的控制下优先并入新合成的端粒中。加入6- 硫代-dG进入端粒诱导DNA损伤并激活先天免疫信号传导，导致细胞死亡。 因为大约90%的GBM表达端粒酶，这是由早期和高度克隆的TERT启动子引起的， 突变，6-硫代-dG代表了克服肿瘤异质性和激活抗肿瘤的令人兴奋的机制 免疫反应。虽然我们已经证明用6-硫代-dG处理诱导端粒DNA损伤， 在端粒酶阳性细胞中，测定6-硫代-dG- 诱导的DNA损伤和先天免疫激活作为药效学（PD）终点尚不清楚， 使用患者来源的异种移植模型严格测定（目的1）。此外，大多数GBM患者 接受替莫唑胺（TMZ）一线治疗，可诱导端粒酶超突变和丢失 复发时的活动。因此，我们将评估6-硫代-dG在先前TMZ治疗后的功效， 鉴定体内治疗抗性的机制（目的1）。根据目标1和目标2中进行的实验， 项目1，我们将建立初步的生物标志物的敏感性和响应6-硫代dG治疗的阶段 在新诊断的端粒酶阳性GBM成人中进行的机会窗试验（Aim 2）。在2- 在6-硫代-dG的一天手术前疗程中，我们将检查GBM组织中可检测到的DNA损伤增加 （主要终点）和免疫应答的激活。这些研究将有助于设计和实施一项 6-硫代-dG的0期试验，确定最有可能从治疗中获益的患者群体，并评估 在新诊断的端粒酶阳性GBM患者中对6-硫代-dG的敏感性和反应。肾小球基底膜 杜克和UTSW的临床试验基础设施，治疗的患者人群多样化，约占 所有美国GBM患者，是本试验的绝佳环境。因此，项目2有助于GTN U19的整体 目标和NCI的目标，开发新的疗法，以改善治疗成人GBM。