Pharmacological targeting of circadian clock components to treat glioblastoma

生物钟通过建立周期性节律来调节生理过程。 生物钟基因控制肿瘤发生过程中改变的关键途径，包括代谢，炎症， 细胞周期、自噬和DNA损伤反应。重要的是，昼夜节律的破坏增加了 癌症风险，并且几种生理振荡途径在癌症中失去其节律性活动。这些 观察结果表明，生物钟机制的药理学调节可以针对 癌症治疗然而，生物钟的药理学干预与新的 癌症预防和治疗的治疗策略还有待证实。该项目提供了一个 使用胶质母细胞瘤的临床前动物模型，通过部署第一代 靶向核受体（NR）亚家族1 D组成员1（NR 1D 1）的化学工具SR9009和SR9011 和NR 1D 2（REV-ERS）。虽然这些小分子比标准治疗药物更有效， 对于胶质母细胞瘤治疗，这种第一代NR配体具有相对较差的药理学活性， 限制效力和患者疾病治疗的一般适用性的特征。因此，实验室 建议优化REV-ERB激动剂并验证其体外对胶质母细胞瘤的抗癌活性 以及单独或与已建立的临床模式组合的临床前体内，以支持 用有限的治疗方法治疗毁灭性疾病的先导分子。

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.