Targeting the Circadian Rhythm in Glioblastoma Stem Cells

胶质母细胞瘤是所有人类癌症中最致命的。目前的治疗包括最大限度的手术 切除术，然后联合放疗和口服化疗（替莫唑胺），以及辅助 替莫唑胺最大电流疗法只能缓解症状。胶质母细胞瘤患者的中位生存期 据报告为15 - 21个月，但这些数据来自年龄有利的患者， 性能状态。复发性胶质母细胞瘤的治疗是有限的，几乎没有证据表明有效的治疗。 治疗失败的原因有很多，包括存在干细胞样肿瘤细胞，称为 胶质母细胞瘤干细胞（GSC）。GSC有助于辐射抗性、化学抗性、侵袭、免疫耐受性和免疫耐受性。 逃逸和血管生成。GSC显示出对特定信号转导途径的依赖性， 表观遗传调控，与代谢重编程有关。 地球上几乎所有的生物体都暴露在由行星的 围绕自己的轴旋转，这反过来导致内在的，可重复的昼夜节律的进化 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CLOCK转录因子的正调控，其中两个 负调控环，其要么转录下调BMAL1，要么结合并抑制 BMAL1：时钟转录复合物。在我们提出的研究中，我们利用初步发现， 昼夜节律机制在维持GSC中发挥不同的细胞和分子作用。我们将 确定通过代谢重编程介导的GSC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，我们正在使用一类新的药物， 生物钟功能这些小分子抑制剂是脑渗透剂，并且可以与其他药物组合。 这些疗法可以产生GSC的协同靶向作用。为了产生最有效的治疗模式，我们 将询问新型靶向治疗的临床前效用， 可以增强传统疗法的疗效。总体而言，拟议的研究将奠定 癌症干细胞生物学中昼夜节律调节的基础， 可能应用于改善肿瘤护理。

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.