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.
The circadian clock appropriately times cellular functions in the context of the twenty-four hour day while weakened circadian regulation is commonly associated with the onset and rapid progression of cancer. We propose to develop specific, non-toxic, potent drugs that activate core circadian clock regulators with the goal of using these new drugs to treat aggressive cancers including glioblastomas.
