Targeting the Circadian Rhythm in Glioblastoma Stem Cells

针对胶质母细胞瘤干细胞的昼夜节律

• 批准号: 10061578
• 负责人: STEVE A KAY
• 金额: $ 10.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10061578
• 关键词: ARNTL gene; Adjuvant; Adopted; Age; Agonist; Alpha Rhythm; Angiogenic Factor; Apoptosis; Attenuated; Binding; Biological Clocks; Brain; Brain Neoplasms; Carbon; Caring; Cell Cycle Arrest; Cell Maintenance; Cells; Cellular Metabolic Process; Chemoresistance; Chromatin; Circadian Rhythms; Citric Acid Cycle; Clinical; Combined Modality Therapy; Complex; Cytolysis; DNA Damage; Data; Dependence; Development; Down-Regulation; Enzymes; Evolution; Excision; Exposure to; Feedback; Foundations; Genes; Genetic Transcription; Glioblastoma; Glioma; Glucose; Hour; Human; Immune; In Vitro; Invaded; Ionizing radiation; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Neurons; Normal Cell; Oncogenic; Operative Surgical Procedures; Oral; Organism; Pathway interactions; Patients; Performance Status; Planet Earth; Planets; Prognosis; Proteins; Radiation therapy; Recurrence; Regulation; Regulatory Pathway; Reporting; Research Project Grants; Resistance; Respiration; Role; Rotation; Signal Transduction Pathway; Testing; Toxic effect; Translating; Treatment Failure; Tricarboxylic Acids; angiogenesis; base; cancer stem cell; cell growth; chemotherapy; chromatin immunoprecipitation; circadian; circadian pacemaker; clinically significant; conventional therapy; cryptochrome; design; effective therapy; empowered; epigenetic regulation; improved; neoplastic cell; nerve stem cell; new therapeutic target; novel; novel therapeutics; palliation; patient response; patient stratification; pre-clinical; radiation resistance; response; self-renewal; small hairpin RNA; small molecule; small molecule inhibitor; stem; stem cell biology; stem cell differentiation; stem cell growth; stem cell proliferation; stem cell self renewal; stem cells; stem-like cell; stemness; targeted agent; temozolomide; therapeutically effective; therapy resistant; transcription factor; tumor

Glioblastomas rank among the most lethal of all human cancers. Current therapy includes maximal surgical resection, followed by combined radiotherapy and oral chemotherapy (temozolomide), and adjuvant temozolomide. Maximal current therapy offers only palliation. Median survival for glioblastoma patients has been reported to be 15-21 months, but these data are derived from patients with favorable age and performance status. Recurrent glioblastoma therapy is limited with little evidence for effective therapy. Treatment failure is derived from numerous causes, including the presence of stem-like tumor cells, called glioblastoma stem cells (GSCs). GSCs contribute to radioresistance, chemoresistance, invasion, immune escape, and angiogenesis. GSCs display dependencies on specific signal transduction pathways and epigenetic regulation, associated with metabolic reprogramming. Almost all living organisms on earth are exposed to a regular 24-hour day-night cycles generated by planet’s rotation around its own axis, which in return leads to the evolution of intrinsic, entrainable circadian rhythm driven by cell autonomous biological clocks. Molecular oscillation of transcriptional circuitry to regulate circadian rhythms include positive regulation by the BMAL1 and CLOCK transcription factors, with two negative regulatory loops that either transcriptionally downregulate BMAL1 or bind and inhibit BMAL1:CLOCK transcriptional complexes. In our proposed studies, we leverage preliminary findings that the circadian rhythm machinery serves distinct cellular and molecular roles in maintenance of GSCs. We will determine the necessity for circadian rhythm regulation in GSCs mediate through metabolic reprogramming and selective activation of oncogenic pathways. To translate these efforts into novel clinical paradigms, we are using a novel class of agents that target circadian clock function. These small molecule inhibitors are brain penetrant and can be combined with other therapies to create synergistic targeting of GSCs. To generate the most effective therapeutic paradigm, we will interrogate the preclinical utility of novel targeted therapies that disrupt the circadian rhythm oscillatory loop that could accentuate the efficacy of conventional therapy. Collectively, the proposed studies will lay the foundation for improved understanding of circadian rhythm regulation in cancer stem cell biology with possible application to improved oncologic care.

胶质母细胞瘤是所有人类癌症中最致命的。当前疗法包括最大手术 切除，然后进行放疗和口服化疗（替莫唑胺），然后调整 替莫唑胺。最大电流疗法仅提供抑制。胶质母细胞瘤患者的中位生存期 据报道为15-21个月，但这些数据来自年龄良好和 性能状态。复发性胶质母细胞瘤疗法受到限制，几乎没有有效治疗的证据。 治疗失败来自许多原因，包括存在称为干肿瘤细胞的原因 胶质母细胞瘤干细胞（GSC）。 GSC有助于放射线，化学抗性，侵袭，免疫 逃生和血管生成。 GSC显示对特定信号传输途径的依赖性和 表观遗传调节，与代谢重编程有关。 地球上几乎所有生物都暴露于星球的常规24小时昼夜周期 围绕其自身的轴旋转，作为回报，这导致了内在的，可夹住的昼夜节律的演变 由细胞自主生物时钟驱动。转录电路的分子振荡以调节 昼夜节律包括BMAL1和时钟转录因子的阳性调节，有两个 负调控环在转录下调BMAL1或结合并抑制 BMAL1：时钟转录复合物。在我们提出的研究中，我们利用了初步发现 昼夜节律机械在维持GSC中起着独特的细胞和分子作用。我们将 确定GSC中昼夜节律调节的必要条件通过代谢重编码进行介导 和致癌途径的选择性激活。 为了将这些努力转化为新型的临床范例，我们正在使用一种针对的新型代理 昼夜节律钟功能。这些小分子抑制剂是脑渗透剂，可以与其他 创建GSC协同靶向的疗法。为了产生最有效的治疗范式，我们 将询问破坏昼夜节律振荡的新型靶向疗法的临床前实用性 可以强调常规治疗效率的循环。总的来说，拟议的研究将进行 改善对癌症干细胞生物学中昼夜节律调节的理解的基础 可能应用以改善肿瘤护理。