Exploiting Epigenetic Vulnerabilities In Glioblastoma Stem Cells Through Reprogramming

通过重编程利用胶质母细胞瘤干细胞的表观遗传漏洞

• 批准号: 10430928
• 负责人: Arnold Etame
• 金额: $ 43.33万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430928
• 关键词: Binding; Biological Assay; CRISPR/Cas technology; Cell Cycle Progression; Clinical Trials; Complex; Cytosol; DNA Repair; DNA Repair Gene; Data; Effectiveness; Endoplasmic Reticulum; Environment; Epigenetic Process; Experimental Models; Foundations; Glioblastoma; Goals; I Kappa B-Alpha; Knock-out; Knowledge; Lentivirus; Leucine Zippers; MGMT gene; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Methylation; Methyltransferase; N-Glycosylation Site; NF-kappa B; Nature; Neurosurgeon; Nuclear Translocation; Operative Surgical Procedures; Patients; Pharmacology; Phosphorylation; Positioning Attribute; Predisposition; Prognosis; Proteins; Regulation; Resistance; Resistance development; Resources; Role; Running; Scientist; Signal Transduction; System; Testing; The Cancer Genome Atlas; Tissues; Transgenes; Translating; Tumor Suppressor Proteins; base; chemotherapy; chromatin immunoprecipitation; design; effective therapy; gain of function; glycosylation; improved; insight; mutant; novel; p65; patient derived xenograft model; prevent; promoter; protein expression; refractory cancer; resistance mechanism; response; single cell sequencing; stem cell model; stem cells; temozolomide; treatment strategy; tumor heterogeneity

Glioblastoma (GBM) is a highly resistant cancer. Temozolomide (TMZ) is the best first-line therapy available, but TMZ response depends on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT methylated (MGMT-M) GBM patients have suppressed MGMT protein expression which leads to TMZ sensitization and prolonged survival. In contrast MGMT unmethylated (MGMT- UM) GBM patients are resistant to TMZ and have much shorter survivals. So far there have been no successful treatments to render MGMT-UM susceptible to TMZ and therefore there is a desperate need for novel treatment strategies for MGMT-UM. Our long-term goal is to devise strategies that can epigenetically reprogram MGMT-UM GBM patients to the TMZ susceptibility of MGMT-M GBM patients. This proposal exploits a novel epigenetic mechanism in GBM stem cells (GSCs) involving Tumor Suppressor Candidate 3 (TUSC3) that can be used to reprogram MGMT-UM to restore sensitivity to TMZ and significantly prolong survival in experimental models of GBMs. The objective in this application is to understand how TUSC3 is epigenetically regulated and how TUSC3 sensitizes GBMs to TMZ. We recently discovered using both pharmacologic epigenetic reprogramming and gain-of-function strategies that: i) TUSC3 promoter regulation in GSCs is impacted by MGMT; ii) TUSC3 significantly sensitized GSCs through suppression of DNA damage repair and cell cycle progression; and iii) TUSC3 synergized with TMZ to produce similar survival benefits in experimental models of MGMT-M and MGMT-UM GBMs. We will therefore test the hypothesis that epigenetic reactivation of TUSC3 reprograms GBMs to TMZ sensitivity and prolonged survival. In Aim 1, we will determine how TUSC3 is epigenetically regulated in GBM. In Aim 2, we will determine how TUSC3 mediates TMZ response sensitization in GBM. Mechanistic knowledge gained from these studies will enhance our understanding of novel epigenetic reprogramming mechanisms in GBM and contribute toward the optimal design of impactful trials for MGMT-UM GBMs who currently do not have good chemotherapy options.

胶质母细胞瘤（GBM）是一种高度抗性的癌症。 Temozolomide（TMZ）是最好的一线疗法， 但是TMZ响应取决于DNA修复基因O6-甲基鸟嘌呤DNA的启动子甲基化状态 甲基转移酶（MGMT）。 MGMT甲基化（MGMT-M）GBM患者已抑制MGMT蛋白 导致TMZ敏化并延长生存的表达。相反，MGMT未甲基化（MGMT- UM）GBM患者对TMZ有抵抗力，并且生存较短。到目前为止还没有 成功的治疗方法使MGMT-UM容易受到TMZ的影响，因此迫切需要 MGMT-UM的新型治疗策略。我们的长期目标是制定可以表观遗传的策略 对MGMT-M GBM患者的TMZ敏感性进行重编程MGMT-UM GBM患者。这个建议 利用GBM干细胞（GSC）的新型表观遗传机制涉及抑制肿瘤候选者3 （TUSC3）可用于重新编程MGMT-UM以恢复对TMZ的敏感性并显着延长 GBMS实验模型中的生存​​。此应用程序的目的是了解Tusc3的状态 表观遗传调节以及TUSC3如何使GBMS对TMZ敏感。我们最近发现了两者 药理学表观遗传学重编程和功能获得策略：i）TUSC3启动子调节 GSC受到MGMT的影响； ii）TUSC3通过抑制DNA损伤显着敏化GSC 修复和细胞周期进程； iii）TUSC3与TMZ协同作用，在 MGMT-M和MGMT-UM GBM的实验模型。因此，我们将测试表观遗传的假设 TUSC3的重新激活将GBM重新编程为TMZ敏感性并延长生存率。在AIM 1中，我们将确定 在GBM中，如何表观遗传调节TusC3。在AIM 2中，我们将确定TUSC3如何介导TMZ GBM中的响应灵敏度。从这些研究中获得的机械知识将增强我们的 了解GBM中新型的表观遗传重编程机制，并有助于最佳 目前没有良好化学疗法的MGMT-UM GBM的有影响力试验设计。