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

项目摘要--项目2 胶质母细胞瘤(GBM)仍然具有一致的致命性，尽管接受了标准的治疗，但总的生存期为21个月。 治疗。免疫疗法在许多癌症中都有显著疗效，但在GBM方面却不太成功。 部分原因是肿瘤的免疫抑制作用和肿瘤内高度的异质性。杜克大学/德克萨斯大学 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 胶质母细胞瘤(GBM)的早期治疗及生物活性研究 临床试验。项目2将通过研究端粒酶反应的生物标记物来为这一目标做出贡献- 靶向剂6-硫代-DG在临床前模型中，并通过进行0期临床试验来检查这些 人类体内的生物标志物。6-硫代-DG是一种血脑屏障(BBB)穿透性嘌呤类似物前药，即 在端粒酶的控制下，优先整合到新合成的端粒中。6-成立为法团 硫代脱氧核糖核酸进入端粒诱导DNA损伤，激活先天免疫信号，导致细胞死亡。 因为大约90%的GBM表达端粒酶是由早期和高度克隆的TERT启动子引起的 突变，6-硫代-DG代表了一种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。尽管我们已经证明，用6-硫代-DG处理会导致端粒DNA损伤和 在端粒酶阳性细胞中诱导免疫介导的细胞毒性，检测6-硫代-DG-2的最佳时间点 作为药效学(PD)终点的诱导DNA损伤和先天免疫激活是未知的，也将是 使用患者来源的异种移植模型进行严格测定(目标1)。此外，大多数GBM患者 接受替莫唑胺(TMZ)的一线治疗，该药可导致端粒酶过度突变和丢失 复发时的活动度。因此，我们将评估6-硫代-DG在先前的TMZ治疗和 确定体内治疗耐药的机制(目标1)。基于在目标1和中进行的实验 项目1，我们将在一个阶段建立对6-硫代-DG治疗敏感性和反应性的初步生物标志物 0对新诊断的、端粒酶阳性的成人GBM的机会窗试验(目标2)。在一次2- 6-硫代-DG手术前一天，我们将检查GBM组织中可检测到的DNA损伤增加 (主要终点)和免疫反应的激活。这些研究将使设计和实施 6-硫代-DG的0期试验，确定最有可能从治疗中受益的患者群体，并评估 新诊断的端粒酶阳性GBM患者对6-硫代-DG的敏感性和反应性。《国税局》 杜克大学和UTSW的临床试验基础设施，治疗占~10%的不同患者群体 所有患有GBM的美国患者，都是这项试验的极佳环境。因此，项目2总体上促成了GTN U19‘S 目标和NCI的目标是开发新的治疗方法来改善成人GBM的治疗。

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.