Pharmacological targeting of circadian clock components to treat glioblastoma

生物钟通过建立周期节律来调节生理过程。 生物钟基因控制着在肿瘤发生过程中改变的关键途径，包括新陈代谢、炎症、 细胞周期、自噬和DNA损伤反应。重要的是，昼夜节律的扰乱增加 癌症风险，几个生理振荡通路在癌症中失去其节律性活动。这些 观察表明，对生物钟机械的药理调节可以针对 癌症治疗。然而，生物钟的药物干预与新的 癌症预防和治疗的治疗策略尚未得到证实。这个项目提供了一个 通过部署第一代胶质母细胞瘤临床前动物模型对概念进行首次验证 针对核受体(NR)亚家族1组D成员1(NR1D1)的化学工具SR9009和SR9011 和NR1D2(Rev-ERSS)。虽然这些小分子比标准的护理药物更有效 对于胶质母细胞瘤的治疗，这第一代NR配体的药理作用相对较差 限制患者疾病治疗的效力和普遍适用性的特点。因此，劳顾会 建议优化REV-ERB激动剂并验证其对胶质母细胞瘤的体外抗癌活性 并在体内单独或与已建立的临床模式相结合的临床前支持翻译 用于治疗破坏性疾病的铅分子，治疗方法有限。

The circadian clock regulates physiologic processes by establishing cyclical rhythms. Circadian clock genes control key pathways altered during tumorigenesis including metabolism, inflammation, cell cycle, autophagy and DNA damage responses. Importantly, disruption of circadian rhythms increases cancer risk, and several physiologically oscillating pathways lose their rhythmic activity in cancer. These observations suggest that pharmacological modulation of the circadian clock machinery can be targeted for cancer treatment. However, the link between pharmacological intervention of the circadian clock and new therapeutic strategies for cancer prevention and treatment has yet to be demonstrated. This project provided a first-proof of concept using a pre-clinical animal model of glioblastoma by deploying the first-generation chemical tools SR9009 and SR9011 targeting nuclear receptor (NR) subfamily 1 group D member 1 (NR1D1) and NR1D2 (REV-ERSs). Although these small molecules were more effective than the standard of care drug for glioblastoma treatment, this first generation of NR ligands have relatively poor pharmacological characteristics limiting potency and general applicability for patient disease treatment. Therefore, the lab proposes to optimize REV-ERB agonists and validate their anticancer activity towards glioblastomas in vitro and pre-clinically in vivo alone or in combination with established clinical modalities to support translation of lead molecules for treating devastating diseases with limited therapeutic treatments.