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）是一种高度耐药的癌症。替莫唑胺 (TMZ) 是目前最好的一线疗法， 但 TMZ 反应取决于 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 患者的 MGMT 蛋白受到抑制 表达导致 TMZ 敏化和延长生存期。相比之下，MGMT 未甲基化 (MGMT- UM) GBM 患者对 TMZ 具有耐药性，并且生存期短得多。到目前为止还没有 成功的治疗使 MGMT-UM 对 TMZ 敏感，因此迫切需要 MGMT-UM 的新治疗策略。我们的长期目标是设计能够表观遗传的策略 将 MGMT-UM GBM 患者重新编程为 MGMT-M GBM 患者的 TMZ 敏感性。这个提议 利用 GBM 干细胞 (GSC) 中涉及肿瘤抑制因子候选 3 的新型表观遗传机制 (TUSC3) 可用于重新编程 MGMT-UM 以恢复对 TMZ 的敏感性并显着延长 GBM 实验模型中的存活率。此应用程序的目的是了解 TUSC3 的作用 表观遗传调控以及 TUSC3 如何使 GBM 对 TMZ 敏感。我们最近发现使用两者 药理学表观遗传重编程和功能获得策略： i) TUSC3 启动子调控 GSC 受 MGMT 影响； ii) TUSC3 通过抑制 DNA 损伤使 GSC 显着敏感 修复和细胞周期进展； iii) TUSC3 与 TMZ 协同作用，在以下疾病中产生类似的生存益处： MGMT-M 和 MGMT-UM GBM 的实验模型。因此，我们将检验表观遗传的假设 TUSC3 的重新激活可将 GBM 重新编程为 TMZ 敏感性并延长生存期。在目标 1 中，我们将确定 TUSC3 在 GBM 中如何受到表观遗传调控。在目标 2 中，我们将确定 TUSC3 如何介导 TMZ GBM 中的反应敏化。从这些研究中获得的机械知识将增强我们的 了解 GBM 中新的表观遗传重编程机制，并有助于实现最佳的 为目前没有良好化疗选择的 MGMT-UM GBM 设计有影响力的试验。