Targeting the Circadian Rhythm in Glioblastoma Stem Cells (R01CA238662)

靶向胶质母细胞瘤干细胞的昼夜节律 (R01CA238662)

基本信息

批准号：
10530615
负责人：
STEVE A KAY
金额：
$ 54.59万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530615
关键词：
ARNTL gene Adjuvant Adopted Age Agonist Angiogenic Factor Apoptosis Attenuated Binding Biological Clocks Brain Brain Neoplasms Carbon Caring Cell Cycle Arrest Cell Maintenance Cells Cellular Metabolic Process Chemoresistance Chemotherapy and/or radiation Chromatin Circadian Dysregulation 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 Process 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 cancer stem cell cell growth chemotherapy chromatin immunoprecipitation circadian circadian pacemaker clinically significant conventional therapy cryptochrome design effective therapy empowerment 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 growth stem cell proliferation stem cell self renewal stem cells stem-like cell stemness synergism targeted agent temozolomide therapeutically effective therapy resistant transcription factor treatment response tumor

项目摘要

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一种，目前的治疗方法包括最大程度的手术。切除，然后联合放疗和口服化疗（替莫唑胺）和辅助治疗替莫唑胺目前的最大治疗只能缓解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适中且复发性胶质母细胞瘤的治疗有限，有效治疗的证据很少。治疗失败的原因有很多，包括干细胞样肿瘤细胞的存在，称为干细胞样肿瘤细胞。胶质母细胞瘤干细胞 (GSC) 有助于放射抗性、化疗抗性、侵袭和免疫。逃逸和血管生成显示出对特定信号转导途径的依赖性。表观遗传调控，与代谢重编程相关。地球上几乎所有的生物体都暴露在由地球产生的有规律的 24 小时昼夜循环中。绕其自身轴旋转，这反过来又导致内在的、可控制的昼夜节律的进化由细胞自主生物钟驱动的转录电路的分子振荡来调节。昼夜节律包括 BMAL1 和 CLOCK 转录因子的正向调节，其中两个负调节环可以转录下调 BMAL1 或结合并抑制 BMAL1:CLOCK 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制在 GSC 的维持中发挥着独特的细胞和分子作用。确定 GSC 通过代谢重编程介导的昼夜节律调节的必要性和选择性激活致癌途径。为了将这些努力转化为新的临床范例，我们正在使用一类针对目标的新型药物这些小分子抑制剂具有脑渗透性，可以与其他药物联合使用。创造 GSC 协同靶向的疗法为了产生最有效的治疗范例，我们将探讨扰乱昼夜节律振荡的新型靶向疗法的临床前效用总的来说，拟议的研究将奠定可能增强传统疗法疗效的循环。为提高对癌症干细胞生物学中昼夜节律调节的理解奠定了基础可能应用于改善肿瘤护理。