Targeting the Circadian Rhythm in Glioblastoma Stem Cells

胶质母细胞瘤是人类所有癌症中最致命的癌症之一。目前的治疗方法包括最大限度的手术治疗 切除，然后联合放疗和口服化疗(替莫唑胺)和辅助 替莫唑胺。最大电流疗法只能起到缓解作用。胶质母细胞瘤患者的中位生存期为 据报道为15-21个月，但这些数据来自年龄和年龄适中的患者 性能状态。复发性胶质母细胞瘤的治疗是有限的，几乎没有有效治疗的证据。 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 胶质母细胞瘤干细胞(GSC)。GSCs参与辐射抵抗、化疗抵抗、侵袭和免疫 逃逸和血管生成。GSC显示对特定信号转导通路的依赖关系 表观遗传调节，与新陈代谢重新编程相关。 地球上几乎所有的生命有机体都暴露在由行星热产生的有规律的24小时昼夜循环中 围绕自己的轴旋转，这反过来又导致内在的、可牵连的昼夜节律的演变 由细胞自主生物钟驱动。转录回路的分子振荡调节 昼夜节律包括BMAL1和时钟转录因子的正调节，有两个 转录下调BMAL1或结合和抑制BMAL1的负性调控环 BMal1：时钟转录复合体。在我们建议的研究中，我们利用了初步研究结果，即 昼夜节律机制在GSCs的维持中起着不同的细胞和分子作用。我们会 确定GSCs通过代谢重编程调节昼夜节律的必要性 以及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，我们正在使用一类新的靶向药物 生物钟功能。这些小分子抑制剂是脑穿透性的，可以与其他 创造GSCs协同靶向的治疗方法。为了产生最有效的治疗范例，我们 将询问打乱昼夜节律振荡的新型靶向治疗的临床前效用 可以加强常规治疗效果的循环。总的来说，拟议的研究将 癌症干细胞生物学中改善昼夜节律调节理解的基础 可能应用于改进的肿瘤护理。

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.