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Pharmacological targeting of circadian clock components to treat glioblastoma

生物钟成分的药理学靶向治疗胶质母细胞瘤

基本信息

批准号：
9897421
负责人：
Satchidananda Panda
金额：
$ 43.63万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897421
关键词：
Agonist Animal Model Apoptotic Autophagocytosis Biological Biological Assay Biological Markers Brain Cell Cycle Cell Line Cell Survival Cell physiology Characteristics Chemicals Circadian Dysregulation Circadian Rhythms Clinical DNA Damage Data Development Disease Generations Genes Glioblastoma Goals Grant Hour Impairment In Vitro Inflammation Intervention Investigation Knock-out Lead Ligands Link Malignant Neoplasms Maps Metabolism Modality Modeling Molecular Nuclear Receptors Pathway interactions Patients Periodicity Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Physiological Processes Plasma Play Property RNA Interference Research Role Structure Structure-Activity Relationship System Therapeutic Time Toxic effect Translating Translations Xenograft procedure affinity labeling analog anticancer activity base cancer cell cancer prevention cancer risk cancer therapy circadian pacemaker circadian regulation design experimental study frontier improved in vivo member metabolomics next generation next generation sequencing novel therapeutic intervention novel therapeutics outcome forecast pharmacophore pre-clinical programs response small molecule standard of care structural biology temozolomide tool tumor tumor progression tumorigenesis

项目摘要

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.

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。